Human Gene Module / Chromosome 16 / SETD1A

SETD1ASET domain containing 1A, histone lysine methyltransferase

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
6 / 15
Rare Variants / Common Variants
34 / 1
EAGLE Score
4.35
Limited Learn More
Aliases
SETD1A, EPEDD,  KMT2F,  Set1,  Set1A
Associated Syndromes
-
Chromosome Band
16p11.2
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Relevance to Autism

De novo missense variants in the SETD1A gene were identified in two ASD probands (Yuen et al., 2017), while a de novo likely gene-disruptive variant in this gene was observed in an ASD proband from the SPARK cohort (Feliciano et al., 2019). Kummeling et al., 2020 reported 15 individuals with de novo SETD1A variants presenting with a novel neurodevelopmental syndrome characterized by global developmental delay and/or intellectual disability, behavioral/psychiatric abnormalities, and craniofacial dysmorphisms; 3/14 individuals in this cohort presented with autistic behavior.

Molecular Function

The protein encoded by this gene is a component of a histone methyltransferase (HMT) complex that produces mono-, di-, and trimethylated histone H3 at Lys4. Trimethylation of histone H3 at lysine 4 (H3K4me3) is a chromatin modification known to generally mark the transcription start sites of active genes. The protein contains SET domains, a RNA recognition motif domain and is a member of the class V-like SAM-binding methyltransferase superfamily.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SETD1A (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
2 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
3 Recent Recommendation Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome Kummeling J et al. (2020) No -
4 Support - Woodbury-Smith M et al. (2022) Yes -
5 Recent Recommendation - Singh T et al. (2022) No -
6 Support - Wang S et al. (2022) No -
7 Support - Carvalho LML et al. (2022) No Autistic features
8 Support - Zhou X et al. (2022) Yes -
9 Support - Spataro N et al. (2023) No Autistic features
10 Positive Association - Jung K et al. (2023) No -
11 Support - Mingping Lan et al. (2023) No -
12 Support - Yasser Al-Sarraj et al. (2024) Yes -
13 Support - Axel Schmidt et al. (2024) No ASD, epilepsy/seizures
14 Support - Hosneara Akter et al. () No -
15 Support - Steven Laurie et al. (2025) Yes -
Rare Variants   (34)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.109C>T p.Gln37Ter stop_gained De novo - - 32346159 Kummeling J et al. (2020)
c.821C>T p.Thr274Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4409-2A>G - splice_site_variant De novo - - 32346159 Kummeling J et al. (2020)
c.2481G>C p.Trp827Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2690G>A p.Arg897Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2968C>G p.Arg990Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1363G>T p.Glu455Ter stop_gained De novo - - 32346159 Kummeling J et al. (2020)
c.1495C>T p.Gln499Ter stop_gained De novo - - 32346159 Kummeling J et al. (2020)
c.2725G>T p.Glu909Ter stop_gained De novo - - 32346159 Kummeling J et al. (2020)
c.2968C>T p.Arg990Ter stop_gained De novo - - 32346159 Kummeling J et al. (2020)
c.3316A>T p.Thr1106Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3935C>T p.Ala1312Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4582-2_4582-1del - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.4618C>T p.Gln1540Ter stop_gained De novo - - 39039281 Axel Schmidt et al. (2024)
c.4582-2_4582del - splice_site_variant De novo - - 32346159 Kummeling J et al. (2020)
c.7C>T p.Gln3Ter stop_gained Unknown Not paternal - 36980980 Spataro N et al. (2023)
c.4169G>A p.Arg1390Gln missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.4495T>G p.Tyr1499Asp missense_variant De novo - - 32346159 Kummeling J et al. (2020)
c.870-10T>G - intron_variant De novo - Unknown 38572415 Yasser Al-Sarraj et al. (2024)
c.4010A>C p.Glu1337Ala missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.3012G>A p.Ser1004= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.252C>T p.Asp84= synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.2740C>T p.Pro914Ser missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.4246G>A p.Glu1416Lys missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.1381dup p.Arg461ProfsTer18 frameshift_variant De novo - - 31452935 Feliciano P et al. (2019)
c.1014dup p.Ala339ArgfsTer23 frameshift_variant De novo - - 32346159 Kummeling J et al. (2020)
c.2289dup p.Val764SerfsTer61 frameshift_variant De novo - - 32346159 Kummeling J et al. (2020)
c.2189A>G p.Tyr730Cys missense_variant Unknown - Unknown 39825153 Steven Laurie et al. (2025)
c.1602_1603del p.Gly535AlafsTer12 frameshift_variant De novo - - 32346159 Kummeling J et al. (2020)
c.3982_3983del p.Phe1328GlnfsTer5 frameshift_variant De novo - - 32346159 Kummeling J et al. (2020)
c.1144_1147del p.Tyr382HisfsTer114 frameshift_variant De novo - - 32346159 Kummeling J et al. (2020)
c.3005_3006del p.Glu1002GlyfsTer20 frameshift_variant De novo - Simplex 37928142 Mingping Lan et al. (2023)
c.3937_3947del p.Pro1313AlafsTer17 frameshift_variant Unknown Not maternal - 32346159 Kummeling J et al. (2020)
c.2761G>A p.Asp921Asn missense_variant Familial Paternal Extended multiplex 35597848 Carvalho LML et al. (2022)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.247-778A>T - intron_variant - - - 37258574 Jung K et al. (2023)
SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
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.

S

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."

4/1/2022
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1

Increased from to 1

Krishnan Probability Score

Score 0.4744237714791

Ranking 8671/25841 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 0.99999623135508

Ranking 380/18225 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
Sanders TADA Score

Score 0.94321299209291

Ranking 15601/18665 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
Zhang D Score

Score 0.14411572466892

Ranking 5293/20870 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
CNVs associated with SETD1A(1 CNVs)
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16p11.2 151 Deletion-Duplication 218  /  1696
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