LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-11
Case ID: NM_022552.4_c.977G_T_20260511_184857
Framework: ACMG/AMP 2015
Variant classification summary

DNMT3A  · NP_072046.2:p.(Arg326Leu)  · NM_022552.4
GRCh37: chr2:25470497 C>A  ·  GRCh38: chr2:25247628 C>A
Gene: DNMT3A Transcript: NM_022552.4
Final call
All criteria require review: For research and educational purposes only.
Variant details
Gene
DNMT3A
Transcript
NM_022552.4
Protein
NP_072046.2:p.(Arg326Leu)
gnomAD AF
3.097770596457142e-06 (v4.1)
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The DNMT3A c.977G>T (p.Arg326Leu; p.R326L) variant has not been reported in 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.
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).
Final determination:
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A This is a missense variant, and available evidence does not indicate a nonsense, frameshift, canonical +/-1 or 2 splice, or other established loss-of-function consequence. SpliceAI predicts no significant splice impact (max delta score 0.00), so PVS1 is not applicable.
pvs1_gene_context pvs1_variant_assessment spliceai
PS1 Not assessed No evidence was identified showing that another nucleotide change produces the same amino acid substitution with an established pathogenic or likely pathogenic interpretation.
PS2 Not assessed No de novo occurrence data were identified for this variant.
PS3 Not assessed Available evidence does not include a well-established functional study demonstrating a damaging effect for p.Arg326Leu. The identified publications provide gene-level DNMT3A functional context but do not document a validated variant-specific assay result for this substitution.
oncokb PMID:23341344 PMID:34429321
PS4 Not assessed No affected-case enrichment or case-control data were identified for this variant.
clinvar gnomad_v2 gnomad_v4
PM1 Not met 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.
hotspots
PM2 Met 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 gnomad_v4
PM3 Not assessed No phase data or recessive-case evidence were identified for this variant.
PM4 N/A This is not a protein length-changing variant.
PM5 N/A Classic same-residue PM5 use could not be confirmed safely for this case, and no established same-residue pathogenic comparator was identified for application here.
pm5_candidates
PM6 Not assessed No presumed de novo report was identified for this variant.
PP1 Not assessed No segregation data were identified for this variant.
PP2 Not assessed Available evidence does not establish a gene-specific missense constraint rule suitable for applying PP2 in this case.
PP3 Met 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 bayesdel spliceai
PP4 Not assessed No phenotype-specific clinical data were provided to assess whether the presentation is highly specific for a DNMT3A-related disorder.
PP5 Not assessed No reputable external pathogenic classification for this exact variant was identified.
clinvar
BA1 Not met Population frequency does not meet the benign stand-alone threshold. The highest observed population frequency is 0.01629% in gnomAD v2.1 Remaining individuals and 0.00223% in gnomAD v4.1 East Asian, both below the 1% BA1 threshold.
gnomad_v2 gnomad_v4
BS1 Not met Population frequency is below the benign strong threshold. The highest observed population frequency is 0.01629% in gnomAD v2.1 and 0.00223% in gnomAD v4.1, both below the 0.3% BS1 threshold.
gnomad_v2 gnomad_v4
BS2 Not met Available population data do not show this variant at a frequency or zygosity pattern sufficient to support observation in healthy adults for BS2.
gnomad_v2 gnomad_v4
BS3 Not assessed Available evidence does not include a well-established functional study demonstrating normal function for p.Arg326Leu.
oncokb PMID:23341344 PMID:34429321
BS4 Not assessed No non-segregation data were identified for this variant.
BP1 Not assessed Available evidence does not support treating missense change as a low-prior mechanism for this gene in a way that would justify BP1.
BP2 Not assessed No phase data were identified to assess BP2.
BP3 N/A This is not an in-frame insertion or deletion in a repetitive region.
BP4 Not met Computational evidence does not support a benign effect. REVEL 0.723 and BayesDel 0.244335 are consistent with a damaging missense effect, although SpliceAI predicts no significant splice impact (max delta score 0.00).
revel bayesdel spliceai
BP5 Not assessed No alternative molecular explanation was provided that would account for the phenotype independently of this variant.
BP6 Not assessed No reputable external benign classification for this exact variant was identified.
clinvar
BP7 N/A This criterion is intended for synonymous or certain intronic variants and is not applicable to this missense change.
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