Final classification

Likely Pathogenic

PVS1PM2

DNMT3A

c.1312dup

p.Asp438GlyfsTer7

This variant

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

Transcript

NM_022552.4

HGVS · transcript:coding

NM_022552.4:c.1312dup

GRCh38

chr2:25246276 T>TC

GRCh37

chr2:25469145 T>TC

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to Likely Pathogenic.

Classification rationale

PVS1PM2 Likely Pathogenic

DNMT3A c.1312dup

The DNMT3A c.1312dup (p.Asp438GlyfsTer7; p.D438Gfs*7) variant has not been reported in ClinVar.¹ 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.² 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.³ 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.⁴

PVS1 + PM2 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 PMID:24614070 ↗pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗

4 spliceai ↗pvs1_variant_assessment

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 · 17 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

PVS1 very strong review Pathogenic

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.

Predicted frameshift with premature terminationGeneric PVS1 gene gate marked eligible for DNMT3APublished germline DNMT3A syndrome literature supports loss of function

pvs1_generic_framework ↗PMID:24614070 ↗

PM2 supporting review Pathogenic

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 v2.1 absentgnomAD v4.1 total AC 0 of AN 1613462

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 4 not met · 13 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with verified maternity and paternity was available for this variant.

PS3 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.

PS4 No case-control enrichment data or multiple independent affected observations for this exact variant were available.

PM1 Available hotspot review did not show this variant in a statistically significant hotspot or established critical region without benign variation.

PM6 No presumed de novo report without confirmed parentage was available for this variant.

PP1 No segregation data were available for this variant.

PP4 No phenotype information was available to determine whether the clinical presentation is highly specific for a DNMT3A-related disorder.

PP5 No external classified record from a qualifying reputable source was available for this exact variant.

Benign

BA1 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.

BS1 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.

BS2 Available population data do not show this variant in healthy adults at a frequency that would support BS2.

BS3 No well-established functional study showing a normal or benign effect for this exact variant was available.

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

BP2 No phase data with another pathogenic variant were available.

BP3 No evidence was available that this variant lies in a repetitive region without known function where small insertions or deletions are common.

BP5 No alternate molecular explanation for the clinical findings was available.

BP6 No qualifying reputable-source benign classification was available for this exact variant.

N/A · 9 PS1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP4 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1613462 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74884 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / 1,613,462
0 hom

Not observed in any ancestry group.

+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 = 0.06).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome

PMID 24614070 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PVS1 very strong

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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