NM_022552.4:c.1312dupG

DNMT3A · NP_072046.2:p.(Asp438GlyfsTer7) · NM_022552.4

GRCh37: chr2:25469145 T>TC · GRCh38: chr2:25246276 T>TC

Gene: DNMT3A Transcript: NM_022552.4

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

DNMT3A

Transcript

NM_022552.4

Protein

NP_072046.2:p.(Asp438GlyfsTer7)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The DNMT3A c.1312dup (p.Asp438GlyfsTer7; p.D438Gfs*7) variant has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, with 0/1613462 alleles observed overall in gnomAD v4.1, which is below the 0.1% non-VCEP PM2 threshold.

Published DNMT3A germline disease literature supports loss of function as a disease mechanism, and this variant is predicted to introduce a premature stop codon through a frameshift, consistent with a truncating effect.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.06, supporting that the main predicted consequence is the frameshift truncation rather than splice disruption.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	This variant is a frameshift, NM_022552.4:c.1312dup, predicted to cause p.Asp438GlyfsTer7 (p.D438Gfs*7). Available gene-level evidence supports loss of function as an established DNMT3A disease mechanism, so a truncating variant of this type meets generic PVS1 criteria.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework PMID:24614070
PS1	N/A	PS1 applies to a different nucleotide change causing the same amino acid substitution. This variant is a frameshift and does not fit that rule.
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was available for this variant.	PMID:24614070 clinvar
PS3	Not assessed	Curated literature relevant to DNMT3A function was available, but no validated functional study for this exact variant was available to support or refute a damaging effect under PS3/BS3.	oncokb PMID:21067377 PMID:24614070 PMID:25964253
PS4	Not assessed	No case-control enrichment data or multiple independent affected observations for this exact variant were available.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	Available hotspot review did not show this variant in a statistically significant hotspot or established critical region without benign variation.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, with 0/1613462 alleles observed overall and 0/74884 alleles in the highest observed subpopulation. The observed population frequency is therefore below the non-VCEP PM2 threshold of 0.1%.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is used for recessive disorders with trans observations. DNMT3A-related overgrowth syndrome is an autosomal dominant condition, so PM3 does not apply.	PMID:24614070
PM4	N/A	PM4 is intended for protein length changes from in-frame insertions/deletions or stop-loss variants. This variant is a frameshift already captured by PVS1 logic.	pvs1_variant_assessment
PM5	N/A	Classic PM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change has been established. This variant is a frameshift, and available PM5 review did not support classic same-residue PM5 use.	pm5_candidates
PM6	Not assessed	No presumed de novo report without confirmed parentage was available for this variant.	PMID:24614070 clinvar
PP1	Not assessed	No segregation data were available for this variant.
PP2	N/A	PP2 is a missense-specific rule and does not apply to this frameshift variant.
PP3	N/A	Available computational evidence does not provide an additional pathogenic prediction beyond the established frameshift consequence. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.06, and REVEL/BayesDel are not applicable to this duplication.	spliceai
PP4	Not assessed	No phenotype information was available to determine whether the clinical presentation is highly specific for a DNMT3A-related disorder.
PP5	Not assessed	No external classified record from a qualifying reputable source was available for this exact variant.	clinvar
BA1	Not met	This variant does not meet BA1 because it is absent from gnomAD v2.1 and absent from gnomAD v4.1; the observed population frequency is 0, well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	This variant does not meet BS1 because it is absent from gnomAD v2.1 and absent from gnomAD v4.1; the observed population frequency is 0, below the 0.3% BS1 threshold used for non-VCEP review.	gnomad_v2 gnomad_v4
BS2	Not met	Available population data do not show this variant in healthy adults at a frequency that would support BS2. No alleles and no homozygotes were observed in gnomAD v4.1.	gnomad_v4
BS3	Not assessed	No well-established functional study showing a normal or benign effect for this exact variant was available.	oncokb PMID:21067377 PMID:24614070 PMID:25964253
BS4	Not assessed	No non-segregation data were available for this variant.
BP1	N/A	BP1 is a missense-specific rule and does not apply to this frameshift variant.
BP2	Not assessed	No phase data with another pathogenic variant were available.
BP3	Not assessed	No evidence was available that this variant lies in a repetitive region without known function where small insertions or deletions are common.
BP4	N/A	SpliceAI predicts no significant splice impact, with a maximum delta score of 0.06, but BP4 does not offset the established truncating consequence of this frameshift variant.	spliceai
BP5	Not assessed	No alternate molecular explanation for the clinical findings was available.
BP6	Not assessed	No qualifying reputable-source benign classification was available for this exact variant.	clinvar
BP7	N/A	BP7 applies to synonymous or certain noncoding variants and does not apply to this frameshift variant.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.