DNMT3ADNA (cytosine-5-)-methyltransferase 3 alpha
Autism Reports / Total Reports
15 / 34Rare Variants / Common Variants
129 / 1Aliases
DNMT3A, DNMT3A2, M.HsaIIIA, TBRSAssociated Syndromes
Tatton-Brown-Rahman syndrome, Heyn-Sproul-Jackson syndrome, DD, Tatton-Brown-Rahman syndrome, DD, Tatton-Brown-Rahman syndrome, ADHD, DD, Tatton-Brown-Rahman syndrome, DD, IDChromosome Band
2p23.3Associated Disorders
SCZ, ID, ASDGenetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, FunctionalRelevance 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. Additional de novo protein-truncating variants and missense variants in the DNMT3A gene were identified in ASD probands from the SPARK cohort (Feliciano et al., 2019) and the Autism Sequencing Consortium (Satterstrom et al., 2020); TADA analysis in both studies identified DNMT3A 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 DNMT3A as a gene reaching exome-wide significance (P < 2.5E-06). Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).
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.
External Links
SFARI Genomic Platforms
Reports related to DNMT3A (34 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 undiagnosed diseases | 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 |
11 | Positive Association | Genetic association of DNMT variants can play a critical role in defining the methylation patterns in autism | Alex AM , et al. (2019) | Yes | - |
12 | Support | Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort | Callaghan DB , et al. (2019) | Yes | - |
13 | Support | Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes | Feliciano P et al. (2019) | Yes | - |
14 | Support | Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients | Tenorio J , et al. (2019) | No | SCZ |
15 | Support | Tatton-Brown-Rahman syndrome: cognitive and behavioural phenotypes | Lane C , et al. (2019) | No | Autistic traits |
16 | Support | Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism | Satterstrom FK et al. (2020) | Yes | - |
17 | Support | Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use | Husson T , et al. (2020) | Yes | - |
18 | Support | Tatton-Brown-Rahman syndrome with a novel DNMT3A mutation presented severe intellectual disability and autism spectrum disorder | Yokoi T et al. (2020) | No | ASD, ID |
19 | Support | - | Smith AM et al. (2021) | No | ASD, ADHD, OCD, DD, ID |
20 | Support | - | Mahjani B et al. (2021) | Yes | - |
21 | Support | - | Bruno LP et al. (2021) | No | - |
22 | Support | - | Leite AJDC et al. (2022) | No | - |
23 | Support | - | Gu T et al. (2022) | No | - |
24 | Support | - | Krgovic D et al. (2022) | Yes | OCD, DD, ID |
25 | Support | - | Levchenko O et al. (2022) | No | - |
26 | Support | - | Zhou X et al. (2022) | Yes | - |
27 | Support | - | Spataro N et al. (2023) | No | Autistic features |
28 | Support | - | Hamagami N et al. (2023) | No | - |
29 | Support | - | Kim GH et al. (2023) | No | - |
30 | Support | - | Mar Jiménez de la Peña et al. (2024) | No | ID, epilepsy/seizures, autistic features |
31 | Recent Recommendation | - | Diana C Beard et al. (2023) | Yes | - |
32 | Support | - | Al-Alya AlSabah et al. (2024) | No | - |
33 | Support | - | Hortense Thomas et al. (2024) | No | - |
34 | Support | - | Axel Schmidt et al. (2024) | Yes | - |
Rare Variants (129)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
- | - | copy_number_loss | Unknown | - | - | 34315901 | Smith AM et al. (2021) | |
- | - | copy_number_loss | De novo | - | - | 35390071 | Leite AJDC et al. (2022) | |
- | - | copy_number_loss | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
- | - | copy_number_loss | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
- | - | frameshift_variant | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
- | p.Arg301Trp | missense_variant | Unknown | - | - | 34315901 | Smith AM et al. (2021) | |
- | p.Arg688His | missense_variant | Unknown | - | - | 34315901 | Smith AM et al. (2021) | |
- | p.Arg736His | missense_variant | Unknown | - | - | 34315901 | Smith AM et al. (2021) | |
- | p.Arg882Cys | missense_variant | Unknown | - | - | 34315901 | Smith AM et al. (2021) | |
- | p.Arg882His | missense_variant | Unknown | - | - | 34315901 | Smith AM et al. (2021) | |
- | p.Cys583Tyr | missense_variant | Unknown | - | - | 34315901 | Smith AM et al. (2021) | |
- | p.Ile310Asn | missense_variant | Unknown | - | - | 34315901 | Smith AM et al. (2021) | |
- | p.Tyr660His | missense_variant | Unknown | - | - | 34315901 | Smith AM et al. (2021) | |
c.1668-1G>A | - | splice_site_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.1015-3C>G | - | splice_region_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.1867-284C>A | - | stop_gained | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
- | p.Phe414fsTer7 | frameshift_variant | Unknown | - | - | 34315901 | Smith AM et al. (2021) | |
c.1211+2T>G | - | splice_site_variant | De novo | - | - | 31685998 | Tenorio J , et al. (2019) | |
c.1681G>T | p.Glu561Ter | stop_gained | De novo | - | - | 31685998 | Tenorio J , et al. (2019) | |
c.1904G>T | p.Arg635Leu | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.1919T>C | p.Phe640Ser | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.2012C>T | p.Thr671Met | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.2050G>A | p.Val684Ile | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.2204A>C | p.Tyr735Ser | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.2711C>T | p.Pro904Leu | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
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) | |
c.1867-254T>C | - | missense_variant | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
c.1523T>C | p.Leu508Pro | missense_variant | Unknown | - | - | 34615535 | Mahjani B et al. (2021) | |
c.1034G>T | p.Cys345Phe | missense_variant | De novo | - | - | 36980980 | Spataro N et al. (2023) | |
c.919C>T | p.Pro307Ser | missense_variant | De novo | - | - | 31685998 | Tenorio J , et al. (2019) | |
c.502C>G | p.Arg168Gly | stop_gained | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
c.580G>A | p.Asp194Asn | stop_gained | 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.427C>T | p.Arg143Ter | stop_gained | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.745C>T | p.Gln249Ter | stop_gained | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.958C>T | p.Arg320Ter | stop_gained | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.1395+3G>C | - | splice_site_variant | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
c.1430-1G>C | - | splice_site_variant | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.556_558+3del | - | splice_site_variant | De novo | - | Simplex | 37303757 | Kim GH et al. (2023) | |
c.745C>T | p.Gln249Ter | stop_gained | De novo | - | Simplex | 32094338 | Husson T , et al. (2020) | |
c.1627G>A | p.Gly543Ser | missense_variant | De novo | - | - | 31685998 | Tenorio J , et al. (2019) | |
c.2207G>A | p.Arg736His | missense_variant | De novo | - | - | 31685998 | Tenorio J , et al. (2019) | |
c.2209C>T | p.Leu737Phe | missense_variant | Unknown | - | - | 31685998 | Tenorio J , et al. (2019) | |
c.1320G>A | p.Trp440Ter | stop_gained | 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.2311C>T | p.Arg771Ter | stop_gained | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.1570C>T | p.Arg524Trp | missense_variant | De novo | - | - | 31452935 | Feliciano P et al. (2019) | |
c.1660G>A | p.Gly554Arg | missense_variant | De novo | - | - | 31452935 | Feliciano P et al. (2019) | |
c.2204A>G | p.Tyr735Cys | missense_variant | De novo | - | - | 25363760 | De Rubeis S , et al. (2014) | |
c.2644C>T | p.Arg882Cys | missense_variant | De novo | - | - | 27479843 | Lelieveld SH et al. (2016) | |
c.2186G>A | p.Arg729Gln | missense_variant | De novo | - | - | 39039281 | Axel Schmidt et al. (2024) | |
c.2206C>T | p.Arg736Cys | missense_variant | De novo | - | - | 39039281 | Axel Schmidt et al. (2024) | |
c.729T>C | p.Thr243= | missense_variant | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
c.2204A>G | p.Tyr735Cys | missense_variant | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
c.1443C>A | p.Tyr481Ter | stop_gained | De novo | - | Simplex | 35887114 | Levchenko O et al. (2022) | |
c.1452G>A | p.Val484= | missense_variant | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
c.699dup | p.Gly234ArgfsTer19 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.1904G>A | p.Arg635Gln | missense_variant | De novo | - | Simplex | 32435502 | Yokoi T et al. (2020) | |
c.541C>T | p.Arg181Cys | 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.892G>T | p.Gly298Trp | 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.929T>A | p.Ile310Asn | missense_variant | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
c.920C>T | p.Pro307Leu | missense_variant | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.1597G>A | p.Gly533Arg | missense_variant | De novo | - | Simplex | 34948243 | Bruno LP et al. (2021) | |
c.1154C>T | p.Pro385Leu | 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.1718A>G | p.Glu573Gly | 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.1943T>C | p.Leu648Pro | missense_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.2188C>T | p.Arg730Cys | 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.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.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.2711C>T | p.Pro904Leu | missense_variant | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
c.1634A>G | p.Glu545Gly | missense_variant | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.1668G>C | p.Arg556Ser | missense_variant | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.1684T>G | p.Cys562Gly | missense_variant | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.1904G>A | p.Arg635Gln | missense_variant | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.1925G>T | p.Gly642Val | missense_variant | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.1976G>A | p.Arg659His | missense_variant | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.2525A>G | p.Gln842Arg | missense_variant | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.2644C>T | p.Arg882Cys | missense_variant | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.2645G>A | p.Arg882His | missense_variant | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.2711C>T | p.Pro904Leu | missense_variant | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.2722T>A | p.Tyr908Asn | missense_variant | De novo | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.1903C>T | p.Arg635Trp | missense_variant | De novo | - | Simplex | 23849776 | Jiang YH , et al. (2013) | |
c.387del | p.Glu129AspfsTer35 | frameshift_variant | De novo | - | - | 36980980 | Spataro N et al. (2023) | |
c.1993G>T | p.Val665Leu | missense_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.892G>T | p.Gly298Trp | missense_variant | De novo | - | - | 27513193 | Farwell Hagman KD , et al. (2016) | |
c.1907C>T | p.Ala636Val | missense_variant | Unknown | - | Simplex | 31038196 | Callaghan DB , et al. (2019) | |
c.1799_1801del | p.Phe600del | inframe_deletion | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
c.1969G>A | p.Val657Met | missense_variant | Unknown | Not maternal | - | 35813072 | Krgovic D et al. (2022) | |
c.1067T>C | p.Leu356Pro | missense_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.1447C>T | p.Arg483Trp | missense_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.1658T>C | p.Ile553Thr | missense_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.1267G>T | p.Glu423Ter | stop_gained | Unknown | Not maternal | - | 38937076 | Hortense Thomas et al. (2024) | |
c.221del | p.Ala74ValfsTer90 | frameshift_variant | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
c.2036G>A | p.Gly679Glu | missense_variant | De novo | - | Simplex | 38041495 | Al-Alya AlSabah et al. (2024) | |
c.2246_2247del | p.Arg749ProfsTer7 | frameshift_variant | De novo | - | - | 31685998 | Tenorio J , et al. (2019) | |
c.421dup | p.Glu141GlyfsTer11 | frameshift_variant | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
c.1925del | p.Gly642GlufsTer9 | frameshift_variant | Unknown | - | - | 38937076 | Hortense Thomas et al. (2024) | |
c.1903C>T | p.Arg635Trp | missense_variant | Familial | Maternal | - | 38937076 | Hortense Thomas et al. (2024) | |
c.1262del | p.Gln421ArgfsTer78 | frameshift_variant | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
c.1505dup | p.Ile503HisfsTer13 | frameshift_variant | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
c.402dup | p.Gly135TrpfsTer17 | frameshift_variant | De novo | - | Simplex | 25363768 | Iossifov I et al. (2014) | |
c.2141+1G>A | - | splice_site_variant | De novo | - | Simplex | 37795572 | Mar Jiménez de la Peña et al. (2024) | |
c.551_553del | p.Pro184_Met185delinsLeu | inframe_deletion | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
c.596_597insGCAA | p.Ser199ArgfsTer18 | frameshift_variant | De novo | - | - | 29900417 | Tatton-Brown K , et al. (2018) | |
c.2207G>A | p.Arg736His | missense_variant | De novo | - | Simplex | 37795572 | Mar Jiménez de la Peña et al. (2024) | |
c.2296_2297del | p.Lys766GlufsTer15 | frameshift_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.1078_1095dup | p.Asn360_Tyr365dup | inframe_insertion | Familial | Maternal | - | 38937076 | Hortense Thomas et al. (2024) | |
c.1127_1128insACGACGACGACGGCTACCAGT | p.Tyr376delinsTer | inframe_insertion | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.1481G>C | p.Cys494Ser | missense_variant | De novo | - | Multiplex (monozygotic twins) | 37795572 | Mar Jiménez de la Peña et al. (2024) |
Common Variants (1)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Paternal Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
c.1717+26C>T;c.2173+26C>T;c.1606+26C>T | - | intron_variant | - | - | - | 30786140 | Alex AM , et al. (2019) |
SFARI Gene score
High Confidence, Syndromic
Score Delta: Score remained at 1S
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."
4/1/2020
Score remained at 1
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. Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).
1/1/2020
Score remained at 1
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. Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).
Reports Added
[Tatton-Brown-Rahman syndrome: cognitive and behavioural phenotypes.2019] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.2020]10/1/2019
Decreased from 3S to 1
New Scoring Scheme
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. Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).
4/1/2019
Decreased from 3S to 3S
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. Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).
1/1/2019
Decreased from 3S to 3S
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. Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).
10/1/2018
Decreased from 3S to 3S
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. Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).
7/1/2018
Decreased from 3 to 3S
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. Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals.
4/1/2017
Decreased from 3 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.
Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose...2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]7/1/2016
Decreased from 3 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.
Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose...2016]10/1/2015
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]
ExAC Score
Score 7.7278751608327E-45
Ranking 18212/18225 scored genes
[Show Scoring Methodology]
Sanders TADA Score
Score 0.016924415179871
Ranking 32/18665 scored genes
[Show Scoring Methodology]
Zhang D Score
Score 0.51065848971063
Ranking 438/20870 scored genes
[Show Scoring Methodology]