Classification rationale

PM2PP3 Unclassified

DNMT3A c.977G>T · exon NC_000002.11

The DNMT3A c.977G>T (p.Arg326Leu; p.R326L) variant has not been reported in ClinVar.¹ This variant is present at very low frequency in gnomAD, with AF 0.00080% (2/251356 alleles) in v2.1 and AF 0.00031% (5/1614064 alleles) in v4.1, both below the 0.1% PM2 threshold.² Computational evidence supports a deleterious missense effect, with REVEL 0.723 and BayesDel 0.244335, while SpliceAI predicts no significant splice impact (max delta score 0.00).³

PM2 + PP3 → Unclassified

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 revelbayesdelspliceai ↗

Gene diagram · NM_022552.4 · variants mapped to exon structure

DNMT3A NM_022552.4

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.09777e-06; MAF= 0.00031%, 5/1614064 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22826e-05; MAF= 0.00223%, 1/44878 alleles, homozygotes = 0).

v2.1

This variant is present in gnomAD v2.1 (AF= 7.95684e-06; MAF= 0.00080%, 2/251356 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000162866; MAF= 0.01629%, 1/6140 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00031% · 5 / 1,614,064
0 hom

East Asian 1 / 44,878	0.0022%
Admixed American 1 / 60,004	0.0017%
Remaining individuals 1 / 62,504	0.0016%
South Asian 1 / 91,078	0.0011%
European (non-Finnish) 1 / 1,179,974	8.5e-05%

+ 5 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0008% · 2 / 251,356
0 hom

Remaining individuals 1 / 6,140	0.016%
East Asian 1 / 18,394	0.0054%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. DNMT3A, a tumor suppressor and DNA methyltransferase, is recurrently mutated in acute myeloid leukemia and other hematologic malignancies.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV53064654, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 2 PMIDs not cited in assessment

23341344 ↗ The molecular profile of adult T-cell acute lymphoblastic leukemia: mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL. ONCOKB

34429321 ↗ Systematic Profiling of DNMT3A Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor. ONCOKB