Human Gene Module / Chromosome 2 / DNMT3A

DNMT3ADNA (cytosine-5-)-methyltransferase 3 alpha

Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
5 / 10
Rare Variants / Common Variants
64 / 0
Aliases
DNMT3A, DNMT3A2,  M.HsaIIIA,  TBRS
Associated Syndromes
Tatton-Brown-Rahman syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
2p23.3
Associated Disorders
ASD
Relevance to Autism

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant.

Molecular Function

The protein encoded by this gene is required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. It plays a role in paternal and maternal imprinting.

Reports related to DNMT3A (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Jiang YH , et al. (2013) Yes -
2 Support Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Tatton-Brown K , et al. (2014) No -
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
4 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
5 Primary Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Sanders SJ , et al. (2015) Yes -
6 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
7 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 -
8 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
9 Recent Recommendation The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants. Tatton-Brown K , et al. (2018) No ASD
10 Support Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions. Heyn P , et al. (2018) No Microcephaly, short stature
Rare Variants   (64)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1903C>T p.Arg635Trp missense_variant De novo - Simplex 23849776 Jiang YH , et al. (2013)
c.2204A>G p.Tyr735Cys missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.403insA p.Gly135fs frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.2711C>T p.Pro904Leu missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.1993G>T p.Val665Leu missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.2644C>T p.Arg882Cys missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.892G>T p.Gly298Trp missense_variant De novo - - 27513193 Farwell Hagman KD , et al. (2016)
c.26_27delinsT - frameshift_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.541C>T p.Arg181Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.759dupC - frameshift_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.889_891delTGG - inframe_deletion De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.892G>T p.Gly298Trp missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.892G>A p.Gly298Arg missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.901C>T p.Arg301Trp missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.918G>A p.Trp306Ter stop_gained De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.929T>A p.Ile310Asn missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.934_937dupTCTT - frameshift_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.941G>A p.Trp314Ter stop_gained De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1015delC - frameshift_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1154C>T p.Pro385Leu missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1296C>G p.Tyr432Ter stop_gained De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1320G>A p.Trp440Ter stop_gained De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1523T>C p.Leu508Pro missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1594G>A p.Gly532Ser missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1594G>A p.Gly532Ser missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1643T>A p.Met548Lys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1643T>C p.Met548Thr missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1645T>C p.Cys549Arg missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1684T>C p.Cys562Arg missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1743G>C p.Trp581Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1743G>C p.Trp581Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1748G>A p.Cys583Tyr missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1803G>A p.Trp601Ter stop_gained De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1851+3G>C p.? splice_site_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1943T>C p.Leu648Pro missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2056delG - frameshift_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2094G>C p.Trp698Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2099C>T p.Pro700Leu missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2141C>G p.Ser714Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2204A>C p.Tyr735Ser missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2207G>A p.Arg736His missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2245C>T p.Arg749Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2245C>T p.Arg749Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2246G>A p.Arg749His missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2255_2257delTCT p.Phe752del inframe_deletion De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2297dupA - frameshift_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2309C>T p.Ser770Leu missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2312G>A p.Arg771Gln missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2401A>G p.Met801Val missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2512A>G p.Asn838Asp missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2644C>T p.Arg882Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2644C>T p.Arg882Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2644C>T p.Arg882Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2645G>A p.Arg882His missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2675C>A p.Ser892Ter stop_gained De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2705T>C p.Phe902Ser missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2711C>T p.Pro904Leu missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2711C>T p.Pro904Leu missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
- - copy_number_loss De novo - - 29900417 Tatton-Brown K , et al. (2018)
- - copy_number_loss De novo - - 29900417 Tatton-Brown K , et al. (2018)
- - copy_number_loss De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.988T>C p.Trp330Arg missense_variant De novo - - 30478443 Heyn P , et al. (2018)
c.988T>C p.Trp330Arg missense_variant De novo - - 30478443 Heyn P , et al. (2018)
c.997G>A p.Asp333Asn missense_variant De novo - - 30478443 Heyn P , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

3

Score Delta: Score remained at 3.1

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

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."

4/1/2017
7/1/2016
3
icon
3

Score remained at 3

Description

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant.

10/1/2015
icon
3

Increased from to 3

Description

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant.

Krishnan Probability Score

Score 0.48601236988581

Ranking 7261/25841 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 7.7278751608327E-45

Ranking 18212/18225 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 0.016924415179871

Ranking 32/18665 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 0.51065848971063

Ranking 438/20870 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 DNMT3A(1 CNVs)
2p23.3 11 Deletion 19  /  66
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