Human Gene Module / Chromosome 3 / SETD5

SETD5SET domain containing 5

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
14 / 40
Rare Variants / Common Variants
130 / 0
EAGLE Score
28.05
Strong Learn More
Aliases
-
Associated Syndromes
-
Chromosome Band
3p25.3
Associated Disorders
DD/NDD, ADHD, ID, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%). Two de novo protein-truncating variants in SETD5 were identified in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; additional protein-truncating variants in this gene were observed in case samples from the Danish iPSYCH study in this report. Furthermore, TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020 identified SETD5 as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified SETD5 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene is predicted to encode a methyltransferase and resides within the critical interval for the 3p25 microdeletion syndrome.

SFARI Genomic Platforms
Reports related to SETD5 (40 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Patterns and rates of exonic de novo mutations in autism spectrum disorders Neale BM , et al. (2012) Yes -
2 Support De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
3 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study Rauch A , et al. (2012) No -
4 Support Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features with further definition of a critical region Kellogg G , et al. (2013) No -
5 Primary De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability Grozeva D , et al. (2014) No OCD, ASD
6 Support Convergence of genes and cellular pathways dysregulated in autism spectrum disorders Pinto D , et al. (2014) Yes -
7 Support Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome Kuechler A , et al. (2014) No -
8 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
9 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
10 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
11 Support Mutations in HECW2 are associated with intellectual disability and epilepsy Halvardson J , et al. (2016) No -
12 Support SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression Szczauba K , et al. (2016) No -
13 Support Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases Farwell Hagman KD , et al. (2016) No -
14 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
15 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) No -
16 Support SETD5 gene variant associated with mild intellectual disability - a case report Stur E , et al. (2017) No -
17 Recent Recommendation Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance Powis Z , et al. (2017) No ADHD, ASD
18 Support Expanding the genetic heterogeneity of intellectual disability Anazi S , et al. (2017) No ADHD
19 Support Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability Zhao JJ , et al. (2017) No Dysmorphic features, MCA
20 Support Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands Jin SC , et al. (2017) No Neurodevelopmental disorders (NDD)
21 Support Exome Pool-Seq in neurodevelopmental disorders Popp B , et al. (2017) No Hypotonia
22 Recent Recommendation Genetic variations on SETD5 underlying autistic conditions Fernandes IR , et al. (2018) No Autistic features
23 Recent Recommendation Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition Deliu E , et al. (2018) No -
24 Support A novel mutation in a common pathogenic gene ( SETD5) associated with intellectual disability: A case report Fang YL , et al. (2019) No DD, ID
25 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
26 Support SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome Crippa M et al. (2020) No ASD
27 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
28 Support - Brunet T et al. (2021) No -
29 Support - Mahjani B et al. (2021) Yes -
30 Support - Hu C et al. (2022) Yes -
31 Support - Zhou X et al. (2022) Yes -
32 Support - Gabellini C et al. (2022) Yes -
33 Support - Spataro N et al. (2023) No ADHD, autistic features
34 Support - Zaghi M et al. (2023) No -
35 Support - Sanchis-Juan A et al. (2023) No -
36 Support - Sheth F et al. (2023) Yes DD, ID
37 Support - et al. () Yes -
38 Support - et al. () No -
39 Support - et al. () No -
40 Support - et al. () No -
Rare Variants   (130)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 38438125 et al. ()
c.2983C>T p.Arg995Ter stop_gained Unknown - - 38438125 et al. ()
- - copy_number_loss De novo - - 25138099 Kuechler A , et al. (2014)
c.*3dup - frameshift_variant De novo - - 33004838 Wang T et al. (2020)
- - copy_number_loss De novo - Unknown 24768552 Pinto D , et al. (2014)
- - copy_number_loss De novo - Simplex 32793091 Crippa M et al. (2020)
c.1282C>T p.Pro428Ser missense_variant Unknown - - 37943464 et al. ()
c.922C>T p.Arg308Ter stop_gained De novo - Simplex 38041506 et al. ()
c.195T>A p.Ser65%3D stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1782+1G>T - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.1576G>T p.Glu526Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.2021T>G p.Leu674Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.2205C>G p.Thr735%3D stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.2644C>T p.Arg882Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
c.2644C>T p.Arg882Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.71+876dup - frameshift_variant De novo - - 28881385 Powis Z , et al. (2017)
c.3520C>T p.Arg1174Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1333C>T p.Arg445Ter stop_gained De novo - - 28991257 Jin SC , et al. (2017)
c.71+2260del - frameshift_variant De novo - - 28881385 Powis Z , et al. (2017)
c.1783-2A>T - splice_site_variant De novo - - 28881385 Powis Z , et al. (2017)
c.2347-7A>G - splice_site_variant De novo - - 28881385 Powis Z , et al. (2017)
c.2476+1G>A - splice_site_variant - - Simplex 28940097 Anazi S , et al. (2017)
c.3196-2A>G - splice_site_variant Familial Both parents - 38177409 et al. ()
c.598G>T p.Glu200Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
c.814C>T p.Gln272Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
c.3001C>T p.Arg1001Ter stop_gained De novo - - 28881385 Powis Z , et al. (2017)
c.625C>T p.Arg209Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.554C>T p.Thr185Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.977T>C p.Leu326Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2347-7A>G - splice_region_variant De novo - - 36980980 Spataro N et al. (2023)
c.1030G>A p.Gly344Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1591C>T p.Arg531Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1663G>A p.Gly555Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1763G>A p.Arg588Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2237C>T p.Pro746Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2269C>T p.Arg757Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2300G>A p.Arg767His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2348G>A p.Arg783His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2416C>T p.Gln806Ter missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2698C>T p.Arg900Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2932C>T p.Arg978Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2933G>A p.Arg978Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2509C>T p.Arg837Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3407C>T p.Ser1136Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3731G>A p.Cys1244Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3929C>T p.Ser1310Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3235A>G p.Lys1079Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4216T>A p.Ser1406Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1967del p.Leu656Ter frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.2734C>T p.Arg912Ter stop_gained Familial Maternal - 33004838 Wang T et al. (2020)
c.1524+1G>A - splice_site_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.2302C>T p.Arg768Ter stop_gained De novo - Simplex 23020937 Rauch A , et al. (2012)
c.2302C>T p.Arg768Ter stop_gained De novo - Simplex 28990276 Zhao JJ , et al. (2017)
c.71+904A>G - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.71+1947_71+1948insA - frameshift_variant De novo - - 28881385 Powis Z , et al. (2017)
c.894A>G p.Ile298Met missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1195A>T p.Lys399Ter stop_gained De novo - Simplex 24680889 Grozeva D , et al. (2014)
c.1043G>A p.Arg348Gln missense_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.2929T>A p.Phe977Ile missense_variant Familial Paternal - 35741772 Hu C et al. (2022)
c.3001C>T p.Arg1001Ter stop_gained De novo - Simplex 24680889 Grozeva D , et al. (2014)
c.922C>T p.Arg308Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.598G>T p.Glu200Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.848G>A p.Arg283Gln missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.2949del p.Met984CysfsTer7 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.4032_4033del p.Ala1345Ter frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1022G>A p.Arg341His missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.1125dup p.Val376CysfsTer9 frameshift_variant De novo - - 29158550 Popp B , et al. (2017)
c.3737G>T p.Ser1246Ile missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.2158G>T p.Glu720Ter stop_gained De novo - Simplex 27334371 Halvardson J , et al. (2016)
c.814C>T p.Gln272Ter stop_gained De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.2476+2T>C - splice_site_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.3929C>T p.Ser1310Leu missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.4106dup p.Ser1370GlufsTer10 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1405G>A p.Val469Ile missense_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.547_567+60del - splice_site_variant De novo - Simplex 25138099 Kuechler A , et al. (2014)
c.2438dup p.Asn814GlufsTer2 frameshift_variant De novo - - 36980980 Spataro N et al. (2023)
- p.Thr552AsnfsTer5 frameshift_variant De novo - - 27513193 Farwell Hagman KD , et al. (2016)
c.3246del p.Ala1083LeufsTer61 frameshift_variant De novo - - 28881385 Powis Z , et al. (2017)
c.2005G>A p.Gly669Arg missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.367C>T p.Arg123Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.952T>C p.Phe318Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1013_1014del p.Val338GlyfsTer7 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1405G>A p.Val469Ile missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1022G>A p.Arg341His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2164C>G p.Pro722Ala missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2307G>T p.Arg769Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2348G>A p.Arg783His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2351G>A p.Trp784Ter missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2920G>C p.Asp974His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2942T>G p.Phe981Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3066_3087dup p.Glu1030ArgfsTer8 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.3773G>C p.Ser1258Thr missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.3305G>A p.Gly1102Asp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3527G>A p.Arg1176Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3635C>T p.Pro1212Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3907G>A p.Ala1303Thr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.71+1186_71+1201del - frameshift_variant Unknown - Not simplex 28940097 Anazi S , et al. (2017)
c.3106C>T XP_005265353.1:p.Arg1036Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3107G>A XP_005265353.1:p.Arg1036Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.959del p.Lys320AsnfsTer15 frameshift_variant De novo - Simplex 32793091 Crippa M et al. (2020)
c.3855dup p.Ser1286LeufsTer37 frameshift_variant De novo - Simplex 28549204 Stur E , et al. (2017)
c.2154del p.Val719LeufsTer18 frameshift_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.1866C>G p.Tyr622Ter stop_gained Unknown Not maternal Simplex 24680889 Grozeva D , et al. (2014)
c.2918C>G p.Ser973Ter stop_gained Familial Paternal Multiplex 27375234 Szczauba K , et al. (2016)
c.31A>G p.Thr11Ala missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1333C>T p.Arg445Ter stop_gained Unknown Not maternal Multiplex 24680889 Grozeva D , et al. (2014)
c.1374A>T p.Ser458= missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.71+1947_71+1948insA - frameshift_variant Familial Maternal Simplex 28881385 Powis Z , et al. (2017)
c.3771dup p.Ser1258GlufsTer65 frameshift_variant De novo - Simplex 24680889 Grozeva D , et al. (2014)
c.3856del p.Ser1286LeufsTer84 frameshift_variant De novo - Simplex 24680889 Grozeva D , et al. (2014)
c.2025_2026del p.Gly676ValfsTer2 frameshift_variant De novo - Simplex 31656537 Fang YL , et al. (2019)
c.1550C>T p.Ala517Val missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1712G>C p.Gly571Ala missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2006G>C p.Gly669Ala missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2006G>C p.Gly669Ala missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2348G>A p.Arg783His missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2348G>A p.Arg783His missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2468A>G p.Asp823Gly missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2653T>C p.Tyr885His missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1573_1574del p.Leu525ArgfsTer17 frameshift_variant De novo - Simplex 32793091 Crippa M et al. (2020)
c.3174G>C p.Gln1058His missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3817A>C p.Ser1273Arg missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4081G>T p.Val1361Phe missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2955T>A p.Tyr985Ter stop_gained Familial Maternal Multi-generational 28881385 Powis Z , et al. (2017)
c.2006G>C p.Gly669Ala missense_variant Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.2177_2178del p.Thr726AsnfsTer39 frameshift_variant De novo - Simplex 24680889 Grozeva D , et al. (2014)
c.4115C>T p.Thr1372Ile missense_variant Familial Paternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.2177_2178del p.Thr726AsnfsTer39 frameshift_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.3531_3534del p.Gly1179AlafsTer10 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.3154G>T p.Gly1052Ter stop_gained De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

1/1/2021
1
icon
1

Score remained at 1

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%).

10/1/2020
1
icon
1

Score remained at 1

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%).

7/1/2020
1
icon
1

Score remained at 1

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%).

1/1/2020
1
icon
1

Score remained at 1

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%).

10/1/2019
1S
icon
1

Score remained at 1

New Scoring Scheme
Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%).

10/1/2018
1S
icon
1S

Score remained at 1S

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%).

10/1/2017
1S
icon
1S

Score remained at 1S

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as “autistic” in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR ? 0.1, meaning that this gene had a ? 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204).

4/1/2017
1S
icon
1S

Score remained at 1S

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as “autistic” in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05< FDR ?0.1, meaning that this gene had a ?90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features with further definition of a critical region.2013] [De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disa...2014] [Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Mutations in HECW2 are associated with intellectual disability and epilepsy.2016] [Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose...2016] [SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [SETD5 gene variant associated with mild intellectual disability - a case report.2017]
1/1/2017
1S
icon
1S

Score remained at 1S

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as “autistic” in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR ?0.1, meaning that this gene had a ?90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

10/1/2016
1S
icon
1S

Score remained at 1S

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as “autistic” in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05

7/1/2016
1S
icon
1S

Score remained at 1S

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as “autistic” in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05

1/1/2016
1S
icon
1S

Score remained at 1S

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as “autistic” in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05

1/1/2015
1S
icon
1S

Score remained at 1S

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as “autistic” in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05

10/1/2014
3S
icon
1S

Decreased from 3S to 1S

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as “autistic” in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05

7/1/2014
No data
icon
3S

Increased from No data to 3S

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as “autistic” in the supplementary material (PMID 24680889).

4/1/2014
No data
icon
3S

Increased from No data to 3S

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as “autistic” in the supplementary material (PMID 24680889).

Krishnan Probability Score

Score 0.49387519752768

Ranking 3940/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99999956377817

Ranking 259/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Iossifov Probability Score

Score 0.903

Ranking 136/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.0025046092460738

Ranking 22/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 62

Ranking 26/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score -0.063610089782681

Ranking 10921/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CEP70 centrosomal protein 70kDa Human Protein Binding 80321 Q8NHQ1
DPPA2 Developmental pluripotency-associated protein 2 Human Protein Binding 151871 Q7Z7J5
miR126-5p microRNA 126 Human RNA Binding 406913 N/A
miR1265p microRNA 126 Human RNA Binding 406913 N/A
PRR20E Proline-rich protein 20E Human Protein Binding 122183 P86478
Submit New Gene

Report an Error