Human Gene Module / Chromosome 3 / SETD5

SETD5SET domain containing 5

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
6 / 22
Rare Variants / Common Variants
68 / 0
Aliases
SETD5, 
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
3p25.3
Associated Disorders
ASD, DD/NDD, ADHD
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).

Molecular Function

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

Reports related to SETD5 (22 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 disa... 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 undiagnose... 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 (4/11 cases), ASD (3/11 cases)
18 Support Expanding the genetic heterogeneity of intellectual disability. Anazi S , et al. (2017) No ADHD (1/2 cases)
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 (10/42 cases)
Rare Variants   (68)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1405G>A p.Val469Ile missense_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.2005G>A p.Gly669Arg missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.2752C>T p.Arg768Ter stop_gained De novo - Simplex 23020937 Rauch A , et al. (2012)
c.1195A>T p.Lys399Ter stop_gained De novo - Simplex 24680889 Grozeva D , et al. (2014)
c.1333C>T p.Arg445Ter stop_gained Unknown Not maternal Multiplex 24680889 Grozeva D , et al. (2014)
c.1866C>G p.Tyr622Ter stop_gained Unknown Not maternal Simplex 24680889 Grozeva D , et al. (2014)
c.2177_2178del p.Thr726AsnfsTer39 frameshift_variant De novo - Simplex 24680889 Grozeva D , et al. (2014)
c.3001C>T p.Arg1001Ter stop_gained De novo - Simplex 24680889 Grozeva D , et al. (2014)
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)
- - copy_number_loss De novo - Unknown 24768552 Pinto D , et al. (2014)
c.547_567+60del p.? splice_site_variant De novo - Simplex 25138099 Kuechler A , et al. (2014)
- - copy_number_loss De novo - - 25138099 Kuechler A , et al. (2014)
- - copy_number_loss De novo - - 25138099 Kuechler A , et al. (2014)
- - copy_number_loss De novo - - 25138099 Kuechler A , et al. (2014)
- - copy_number_loss De novo - - 25138099 Kuechler A , et al. (2014)
c.922C>T p.Arg308Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1405G>A p.Val469Ile missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.3773G>C p.Ser1258Thr missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2054G>A p.Arg685His missense_variant Familial Paternal (n=1), maternal (n=1) Simplex 25363760 De Rubeis S , et al. (2014)
c.1712G>C p.Gly571Ala missense_variant Familial Paternal (n=2), maternal (n=1) Simplex 25363760 De Rubeis S , et al. (2014)
c.1712G>C p.Gly571Ala missense_variant Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.2359T>C p.Tyr787His missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3174G>C p.Gln1058His missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3523A>C p.Ser1175Arg missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.31A>G p.Thr11Ala missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2174A>G p.Asp725Gly missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1374A>T p.Glu458Asp missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1550C>T p.Pro517Leu missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3787G>T p.Val1263Phe missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3821C>T p.Thr1274Ile missense_variant Familial Paternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.304G>T p.Glu102Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.728G>A p.Arg243His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2054G>A p.Arg685His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3011G>A p.Gly1004Asp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3233G>A p.Arg1078Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3635C>T p.Ser1212Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.658T>C p.Phe220Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1870C>G p.Pro624Ala missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2351G>A p.Arg784Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2999T>G p.Phe1000Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3613G>A p.Ala1205Thr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.367C>T p.Arg123Trp 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.2920G>C p.Asp974His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3154G>T p.Gly1052Ter stop_gained De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.2158G>T p.Glu720Ter stop_gained De novo - Simplex 27334371 Halvardson J , et al. (2016)
c.2918C>G p.Ser973Ter stop_gained Familial Paternal Multi-generational 27375234 Szczauba K , et al. (2016)
- p.Thr552AsnfsTer5 frameshift_variant De novo - - 27513193 Farwell Hagman KD , et al. (2016)
c.1524+1G>A p.? splice_site_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.749G>A p.Arg250Gln missense_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.3848_3849insC p.Ser1286Leufs frameshift_variant De novo - Simplex 28549204 Stur E , et al. (2017)
c.1655_1656insA p.Pro553SerfsTer4 frameshift_variant De novo - - 28881385 Powis Z , et al. (2017)
c.1783-2A>T p.? splice_site_variant De novo - - 28881385 Powis Z , et al. (2017)
c.3001C>T p.Arg1001Ter stop_gained De novo - - 28881385 Powis Z , et al. (2017)
c.582dupA p.Ala195SerfsTer6 frameshift_variant De novo - - 28881385 Powis Z , et al. (2017)
c.2347-7A>G p.? splice_site_variant De novo - - 28881385 Powis Z , et al. (2017)
c.2347-7A>G p.? splice_site_variant De novo - - 28881385 Powis Z , et al. (2017)
c.1967delT p.Leu656Ter frameshift_variant De novo - - 28881385 Powis Z , et al. (2017)
c.3246delT p.Ala1083LeufsTer61 frameshift_variant De novo - - 28881385 Powis Z , et al. (2017)
c.1655_1656insA p.Pro553SerfsTer4 frameshift_variant Familial Maternal Multi-generational 28881385 Powis Z , et al. (2017)
c.2347-7A>G p.? splice_site_variant De novo - - 28881385 Powis Z , et al. (2017)
c.2955T>A p.Tyr985Ter stop_gained Familial Maternal Multi-generational 28881385 Powis Z , et al. (2017)
c.892_907del p.Ile298GlyfsTer32 frameshift_variant Unknown - Familial 28940097 Anazi S , et al. (2017)
c.2476+1G>A p.? splice_site_variant - - Simplex 28940097 Anazi S , et al. (2017)
c.2302C>T p.Arg768Ter stop_gained De novo - Simplex 28990276 Zhao JJ , et al. (2017)
C>T p.Arg347Ter stop_gained De novo - - 28991257 Jin SC , et al. (2017)
c.1125dup p.Val376CysfsTer9 frameshift_variant De novo - - 29158550 Popp B , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

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%).

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."

1/1/2018
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
[SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.2016] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disa...2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.2014] [Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose...2016] [Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features with further definition of a critical region.2013] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Mutations in HECW2 are associated with intellectual disability and epilepsy.2016] [Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.2014] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [SETD5 gene variant associated with mild intellectual disability - a case report.2017] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [De novo gene disruptions in children on the autistic spectrum.2012]
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

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.
CNVs associated with SETD5(1 CNVs)
3p25.3 18 Deletion-Duplication 30  /  87
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
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