SETD1ASET domain containing 1A, histone lysine methyltransferase
Autism Reports / Total Reports
4 / 8Rare Variants / Common Variants
27 / 0Aliases
SETD1A, EPEDD, KMT2F, Set1, Set1AAssociated Syndromes
-Chromosome Band
16p11.2Associated Disorders
-Genetic Category
Rare Single Gene Mutation, Syndromic, FunctionalRelevance 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
SFARI Genomic Platforms
Reports related to SETD1A (8 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 | - |
Rare Variants (27)
| 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 | NA | - | 32346159 | Kummeling J et al. (2020) | |
| c.821C>T | p.Thr274Met | missense_variant | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.4409-2A>G | - | splice_site_variant | De novo | NA | - | 32346159 | Kummeling J et al. (2020) | |
| c.2481G>C | p.Trp827Cys | missense_variant | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.2690G>A | p.Arg897Gln | missense_variant | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.2968C>G | p.Arg990Gly | missense_variant | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.1363G>T | p.Glu455Ter | stop_gained | De novo | NA | - | 32346159 | Kummeling J et al. (2020) | |
| c.1495C>T | p.Gln499Ter | stop_gained | De novo | NA | - | 32346159 | Kummeling J et al. (2020) | |
| c.2725G>T | p.Glu909Ter | stop_gained | De novo | NA | - | 32346159 | Kummeling J et al. (2020) | |
| c.2968C>T | p.Arg990Ter | stop_gained | De novo | NA | - | 32346159 | Kummeling J et al. (2020) | |
| c.3316A>T | p.Thr1106Ser | missense_variant | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.3935C>T | p.Ala1312Val | missense_variant | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.4582-2_4582-1del | - | splice_site_variant | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.4582-2_4582del | - | splice_site_variant | De novo | NA | - | 32346159 | Kummeling J et al. (2020) | |
| c.4495T>G | p.Tyr1499Asp | missense_variant | De novo | NA | - | 32346159 | Kummeling J et al. (2020) | |
| c.252C>T | p.Asp84%3D | synonymous_variant | Unknown | - | - | 35205252 | Woodbury-Smith M et al. (2022) | |
| c.3012G>A | p.Ser1004%3D | synonymous_variant | De novo | NA | Simplex | 35982159 | Zhou X et al. (2022) | |
| c.2740C>T | p.Pro914Ser | missense_variant | De novo | NA | Simplex | 28263302 | C Yuen RK et al. (2017) | |
| c.4246G>A | p.Glu1416Lys | missense_variant | De novo | NA | Multiplex | 28263302 | C Yuen RK et al. (2017) | |
| c.1381dup | p.Arg461ProfsTer18 | frameshift_variant | De novo | NA | - | 31452935 | Feliciano P et al. (2019) | |
| c.1014dup | p.Ala339ArgfsTer23 | frameshift_variant | De novo | NA | - | 32346159 | Kummeling J et al. (2020) | |
| c.2289dup | p.Val764SerfsTer61 | frameshift_variant | De novo | NA | - | 32346159 | Kummeling J et al. (2020) | |
| c.1602_1603del | p.Gly535AlafsTer12 | frameshift_variant | De novo | NA | - | 32346159 | Kummeling J et al. (2020) | |
| c.3982_3983del | p.Phe1328GlnfsTer5 | frameshift_variant | De novo | NA | - | 32346159 | Kummeling J et al. (2020) | |
| c.1144_1147del | p.Tyr382HisfsTer114 | frameshift_variant | De novo | NA | - | 32346159 | Kummeling J et al. (2020) | |
| 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
No common variants reported.
SFARI Gene score
1S
High Confidence, Syndromic
Score Delta: Score remained at 1
criteria met
See SFARI Gene'scoring criteriaWe 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."
4/1/2022
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.
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
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).
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.
CNVs associated with SETD1A(1 CNVs)
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| 16p11.2 | 131 | Deletion-Duplication | 198 / 1618 |