DNMT3A

Chr 2

DNA methyltransferase 3 alpha

Also known as: DNMT3A-3, DNMT3A2, HESJAS, M.HsaIIIA, TBRS

NCBI Gene: 1788 ENSG00000119772 UniProt: Q9Y6K1

The protein functions as a de novo DNA methyltransferase that establishes genome-wide DNA methylation patterns essential for normal development, genomic imprinting, and transcriptional regulation. Germline mutations cause Tatton-Brown-Rahman syndrome and Heyn-Sproul-Jackson syndrome, both presenting with intellectual disability, overgrowth, and distinctive facial features, while somatic mutations are associated with acute myeloid leukemia. Inheritance is autosomal dominant, and the gene shows very low constraint against loss-of-function variants.

ResearchSummary from RefSeq, OMIM, UniProt

CpG methylation is an epigenetic modification that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a DNA methyltransferase that is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes to the cytoplasm and nucleus and its expression is developmentally regulated. [provided by RefSeq, Mar 2016]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtTatton-Brown-Rahman syndrome

UniProtLeukemia, acute myelogenous

UniProtHeyn-Sproul-Jackson syndrome

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Curated mechanisms (Gene2Phenotype) include both loss of function and gain of function. Which applies is variant-dependent — do not assume a null variant is, or isn’t, the pathogenic class without checking the specific variant.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

901

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.58

LOEUF

Multiple*

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

1.58LOEUF

pLI 0.000

Z-score -1.52

OE 1.26 (1.00–1.58)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

3.45Z-score

OE missense 0.59 (0.54–0.65)

339 obs / 570.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?1.26 (1.00–1.58)

0≤0.351.4

Missense OE?0.59 (0.54–0.65)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 52 / 41.4Missense obs/exp: 339 / 570.7Syn Z: 0.63

Background carrier burden — how many people carry a rare variant somewhere in DNMT3A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

1,146 rare PASS variants

Rare truncating (LoF)

1 in 310

902 rare PASS variants

Rare synonymous (reference)

1 in 84

477 rare PASS variants

Rare missense and truncating variants are carried at similar rates in DNMT3A; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 280
South Asian	~43k	1 in 93	1 in 560
Remaining (unassigned)	~30k	1 in 110	1 in 350
European (Finnish)	~27k	1 in 160	1 in 480
Admixed American	~22k	1 in 100	1 in 450
African / African American	~21k	1 in 90	1 in 270
East Asian	~20k	1 in 120	1 in 510
Ashkenazi Jewish	~13k	1 in 96	1 in 100
Middle Eastern	~2,884	1 in 110	1 in 580

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 22 coding exons well covered in gnomAD exomes and genomes.? see exons ↓