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LYFE SCIENCES
Project: HERA
NM_022552.4:c.977G>T
p.Arg326Leu  ·  DNMT3A
ACMG/AMP
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Classification rationale
1

The DNMT3A c.977G>T (p.Arg326Leu; p.R326L) variant has not been reported in ClinVar.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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).

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1This 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).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV53064654, n = 2 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueR326
Hotspots ↗