SETD5SET domain containing 5

SFARI Gene Score

High Confidence, Syndromic Criteria 1.1, Syndromic

Autism Reports / Total Reports

16 / 43

Rare Variants / Common Variants

134 / 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

GPF browser SFARI genome browser

Reports (43)
Variants (134)
Gene Score
Protein Interactions (5)

Reports related to SETD5 (43 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	-	Karthika Ajit Valaparambil et al. ()	Yes	-
38	Support	-	Erica Rosina et al. (2024)	No	-
39	Support	-	M Cecilia Poli et al. ()	No	-
40	Support	-	Tamam Khalaf et al. (2024)	No	-
41	Support	-	Ruohao Wu et al. (2024)	Yes	-
42	Support	-	Laura E Burnett et al. ()	Yes	-
43	Support	-	Axel Schmidt et al. (2024)	No	-

Rare Variants (134)

Allele Change	Residue Change	Variant Type	Inheritance Pattern	Parental Transmission	Family Type	PubMed ID	Author, Year
-	-	copy_number_loss	De novo	-	-	25138099	Kuechler A , et al. (2014)
-	-	copy_number_loss	Unknown	-	-	38438125	Tamam Khalaf et al. (2024)
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.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.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.1783-2A>G	-	splice_site_variant	De novo	-	-	39039281	Axel Schmidt et al. (2024)
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.2983C>T	p.Arg995Ter	stop_gained	Unknown	-	-	38438125	Tamam Khalaf et al. (2024)
c.2302C>T	p.Arg768Ter	stop_gained	De novo	-	-	39039281	Axel Schmidt et al. (2024)
c.1967del	p.Leu656Ter	frameshift_variant	De novo	-	-	33004838	Wang T et al. (2020)
c.3556C>T	p.Arg1186Ter	stop_gained	De novo	-	-	39039281	Axel Schmidt et al. (2024)
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.922C>T	p.Arg308Ter	stop_gained	De novo	-	Simplex	38041506	Erica Rosina et al. (2024)
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)
c.3196-2A>G	-	splice_site_variant	Familial	Both parents	-	38177409	M Cecilia Poli et al. ()
-	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.1282C>T	p.Pro428Ser	missense_variant	Unknown	-	-	37943464	Karthika Ajit Valaparambil et al. ()
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.3855dup	p.Ser1286LeufsTer37	frameshift_variant	De novo	-	Simplex	38764027	Ruohao Wu et al. (2024)
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.

Current Score
Scoring History
3rd Party Scoring

SFARI Gene score

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met

See SFARI Gene'scoring criteria

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.

Syndromic

See all Category S Genes

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

Score remained at 1

Description

Reports Added

[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]

10/1/2020

Score remained at 1

Description

Reports Added

[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]

7/1/2020

Score remained at 1

Description

Reports Added

[SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome2020]

1/1/2020

Score remained at 1

Description

Reports Added

[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]

10/1/2019

Score remained at 1

New Scoring Scheme

Description

Reports Added

[A novel mutation in a common pathogenic gene (SETD5) associated with intellectual disability: A case report.2019] [New Scoring Scheme]

10/1/2018

Score remained at 1S

Description

Reports Added

[Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition.2018]

10/1/2017

Score remained at 1S

Description

Reports Added

[Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance.2017] [Expanding the genetic heterogeneity of intellectual disability.2017] [Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability.2017] [Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.2017] [Exome Pool-Seq in neurodevelopmental disorders.2017]

4/1/2017

Score remained at 1S

Description

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

Score remained at 1S

Description

Reports Added

[Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017]

10/1/2016

Score remained at 1S

Description

Reports Added

[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]

7/1/2016

Score remained at 1S

Description

Reports Added

[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]

1/1/2016

Score remained at 1S

Description

Reports Added

1/1/2015

Score remained at 1S

Description

Reports Added

[Large-scale discovery of novel genetic causes of developmental disorders.2014]

10/1/2014

Decreased from 3S to 1S

Description

Reports Added

[Synaptic, transcriptional and chromatin genes disrupted in autism.2014]

7/1/2014

No data

Increased from No data to 3S

Description

4/1/2014

No data

Increased from No data to 3S

Description

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.

Original Source

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

Original Source

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 Washingtonâs 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

Original Source

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).

Original Source

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.

Original Source

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.

Original Source

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

Human Gene Module / Chromosome 3 / SETD5

SETD5SET domain containing 5

SFARI Gene Score

Autism Reports / Total Reports

Rare Variants / Common Variants

EAGLE Score

Aliases

Associated Syndromes

Chromosome Band

Associated Disorders

Genetic Category

Relevance to Autism

Molecular Function

External Links

Human

Mouse

SFARI Genomic Platforms

Reports related to SETD5 (43 Reports)

Rare Variants (134)

Common Variants

SFARI Gene score

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met

High Confidence

Syndromic

1/1/2021

Score remained at 1

Description

Reports Added

10/1/2020

Score remained at 1

Description

Reports Added

7/1/2020

Score remained at 1

Description

Reports Added

1/1/2020

Score remained at 1

Description

Reports Added

10/1/2019

Score remained at 1

New Scoring Scheme

Description

Reports Added

10/1/2018

Score remained at 1S

Description

Reports Added

10/1/2017

Score remained at 1S

Description

Reports Added

4/1/2017

Score remained at 1S

Description

Reports Added

1/1/2017

Score remained at 1S

Description

Reports Added

10/1/2016

Score remained at 1S

Description

Reports Added

7/1/2016

Score remained at 1S

Description

Reports Added

1/1/2016

Score remained at 1S

Description

Reports Added

1/1/2015

Score remained at 1S

Description

Reports Added

10/1/2014