Classification rationale

PVS1PM2 Likely Pathogenic

DNMT3A c.1792C>T nonsense · exon 15

PVS1 (very strong): the premature stop at p.Arg598Ter is predicted to trigger nonsense-mediated decay. PM2 (supporting): the variant is rare in gnomAD, with AF 2.85054e-05 and zero homozygotes.

PVS1 + PM2 → Likely Pathogenic

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 · 15 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 Pathogenic

Met at very strong: c.1792C>T creates p.Arg598Ter in exon 15, 806 coding bases before the final exon, predicting nonsense-mediated decay.

The case-specific gene context identifies DNMT3A loss of function as a supported germline disease mechanism and marks the generic PVS1 gene gate eligible.Variant validation identifies NM_022552.4 as the RefSeq-selected DNMT3A transcript, with NM_022552.4:c.1792C>T in exon 15 and predicted NP_072046.2:p.(Arg598Ter).The transcript model places the affected exon at c.1668-c.1851 and the terminal exon at c.2598-c.*1318; the premature stop at c.1792 is therefore 806 coding bases before the terminal exon and is not predicted to escape nonsense-mediated decay.

pvs1_generic_framework ↗

PM2 supporting Pathogenic

Met at supporting strength: gnomAD v4.1 AF 2.85054e-05 is below the PM2 threshold of <=0.0001, with zero homozygotes.

gnomAD v4.1 reports AF 2.85054e-05, 46/1,613,732 alleles, 0 homozygotes, and grpmax FAF 2.394e-05; its highest subpopulation AF is 3.37792e-05 in Ashkenazi Jewish individuals.gnomAD v2.1 exomes report AF 2.39469e-05, 6/250,554 alleles, 0 homozygotes, and grpmax FAF 7.04e-06.The supplied generic PM2 calibration is <=0.0001 and PM2 is supporting strength under the stated SVI default (PMID:25741868).

gnomad_v4 ↗gnomad_v2 ↗PMID:25741868 ↗

Assessed · not applied · 4 not met · 11 not assessed

Pathogenic

PS2 Not assessed: parental testing confirming this exact variant as de novo is not documented.

PS3 Not assessed: no validated assay provides a variant-specific functional measurement for DNMT3A p.Arg598Ter.

PS4 Not assessed: no exact-variant case-control enrichment or variant-specific affected-case count is available for PS4.

PM6 Not assessed: neither presumed de novo status nor supporting proband evidence is documented for this exact variant.

PP1 Not assessed: no informative family genotypes or cosegregation data are documented for this exact variant.

PP4 Not assessed: the individual’s documented phenotype is insufficiently specific to confirm PP4 for this exact variant.

PP5 Not met: the exact ClinVar record has 0 expert-panel submissions, despite aggregate Pathogenic/Likely pathogenic laboratory labels.

Benign

BA1 Not met: gnomAD v4.1 AF 2.85054e-05 is far below the generic BA1 threshold of >=0.05, with zero observed homozygotes.

BS1 Not met: the highest gnomAD v4.1 frequency is 3.37792e-05, far below the generic BS1 threshold of >=0.01.

BS2 Not assessed: gnomAD shows zero homozygotes but does not establish healthy-adult status or sufficient penetrance evidence for BS2.

BS3 Not assessed: no validated controlled assay demonstrates preserved function for DNMT3A p.Arg598Ter.

BS4 Not assessed: no unaffected carrier or other exact-variant non-segregation evidence is documented.

BP2 Not assessed: no affected-proband second-variant or phase observation is documented for c.1792C>T.

BP5 Not assessed: no documented alternative molecular cause independently explaining the phenotype is available for BP5.

BP6 Not met: the exact ClinVar record has 0 expert-panel submissions and no Benign or Likely benign expert-panel classification.

N/A · 11 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · 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= 2.85054e-05; MAF= 0.00285%, 46/1613732 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37792e-05; MAF= 0.00338%, 1/29604 alleles, homozygotes = 0); grpmax FAF= 2.394e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 2.39469e-05; MAF= 0.00239%, 6/250554 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.94629e-05; MAF= 0.00995%, 1/10054 alleles, homozygotes = 0); grpmax FAF= 7.04e-06.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0029% · 46 / 1,613,732
0 hom · FAF 0.0024%

Ashkenazi Jewish 1 / 29,604	0.0034%
Admixed American 2 / 60,020	0.0033%
South Asian 3 / 91,080	0.0033%
European (non-Finnish) 38 / 1,179,886	0.0032%
Remaining individuals 1 / 62,478	0.0016%
African/African American 1 / 75,024	0.0013%

+ 4 not observed (European (Finnish), Amish, East Asian, Middle Eastern)

gnomAD v2.1

0.0024% · 6 / 250,554
0 hom · FAF 0.0007%

Ashkenazi Jewish 1 / 10,054	0.0099%
African/African American 1 / 16,082	0.0062%
South Asian 1 / 30,610	0.0033%
European (non-Finnish) 3 / 113,196	0.0027%

+ 4 not observed (Admixed American, East Asian, European (Finnish), Remaining individuals)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 1070654)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). BayesDel score = 0.66.

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 previously been reported in somatic cancers (COSMIC; COSV53039812, n = 17 times).

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. 4 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 4 PMIDs not cited in assessment

24614070 ↗ Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. ONCOKB

21067377 ↗ DNMT3A mutations in acute myeloid leukemia. ONCOKB

25964253 ↗ Simpson's Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia. ONCOKB

35771960 ↗ Tatton-Brown-Rahman Syndrome. CLINVAR

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