Starting

Initialising…

DNMT3A

Final classification

Likely Pathogenic

DNMT3A c.1312dup · p.Asp438GlyfsTer7

DNMT3A

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

Gene

DNMT3A

Transcript

NM_022552.4

HGVS · transcript:coding

NM_022552.4:c.1312dup

Consequence

N/A

GRCh38

chr2:25246276 T>TC

GRCh37

chr2:25469145 T>TC

Basis 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. ▾

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

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

DNMT3A NM_022552.4

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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.

PMID PMID:24614070

PMID PMID:24614070 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PVS1 supports · met

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots