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 ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

DNMT3A NM_022552.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 moderate Pathogenic

This variant is present at very low frequency in population databases, with gnomAD v2.1 AF 0.00080% (2/251356 alleles) and gnomAD v4.1 AF 0.00031% (5/1614064 alleles), both below the 0.1% PM2 threshold.

gnomAD v2.1 total AF 7.95684e-06gnomAD v4.1 total AF 3.09777e-06

gnomad_v2 ↗gnomad_v4 ↗

PP3 supporting Pathogenic

Computational evidence supports a deleterious missense effect. REVEL is 0.723 and BayesDel is 0.244335, both consistent with a damaging protein effect, while SpliceAI predicts no significant splice impact (max delta score 0.00).

REVEL 0.723BayesDel 0.244335SpliceAI max delta score 0.00

spliceai ↗

Assessed · not applied · 5 not met · 16 not assessed

Pathogenic

PS1 No evidence was identified showing that another nucleotide change produces the same amino acid substitution with an established pathogenic or likely pathogenic interpretation.

PS2 No de novo occurrence data were identified for this variant.

PS3 Available evidence does not include a well-established functional study demonstrating a damaging effect for p.Arg326Leu.

PS4 No affected-case enrichment or case-control data were identified for this variant.

PM1 This variant does not lie in a statistically significant hotspot, and available evidence is insufficient to show that codon 326 is within a mutational hotspot or other well-established critical region without benign variation for generic PM1 use.

PM3 No phase data or recessive-case evidence were identified for this variant.

PM6 No presumed de novo report was identified for this variant.

PP1 No segregation data were identified for this variant.

PP2 Available evidence does not establish a gene-specific missense constraint rule suitable for applying PP2 in this case.

PP4 No phenotype-specific clinical data were provided to assess whether the presentation is highly specific for a DNMT3A-related disorder.

PP5 No reputable external pathogenic classification for this exact variant was identified.

Benign

BA1 Population frequency does not meet the benign stand-alone threshold.

BS1 Population frequency is below the benign strong threshold.

BS2 Available population data do not show this variant at a frequency or zygosity pattern sufficient to support observation in healthy adults for BS2.

BS3 Available evidence does not include a well-established functional study demonstrating normal function for p.Arg326Leu.

BS4 No non-segregation data were identified for this variant.

BP1 Available evidence does not support treating missense change as a low-prior mechanism for this gene in a way that would justify BP1.

BP2 No phase data were identified to assess BP2.

BP4 Computational evidence does not support a benign effect.

BP5 No alternative molecular explanation was provided that would account for the phenotype independently of this variant.

BP6 No reputable external benign classification for this exact variant was identified.

N/A · 5 PVS1 · PM4 · PM5 · BP3 · BP7

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

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