PVS1 (very strong): NM_022552.4:c.1154delC is a frameshift deletion introducing a premature termination codon at position 406 (NP_072046.2:p.Pro385ArgfsTer22) in exon 10 of 22 coding exons, predicted to trigger nonsense-mediated decay. DNMT3A loss of function is an established disease mechanism for Tatton-Brown-Rahman syndrome, with a ClinGen haploinsufficiency score of 3.1 PM2 (moderate): The variant is absent from gnomAD v2.1 (0/250,600 alleles) and present at extremely low frequency in gnomAD v4.1 (6/1,613,666 alleles; AF=3.72e-06). The highest subpopulation frequency is 1.67e-05 in the Admixed American population, well below the 0.1% PM2 threshold.2 Combined classification: One very strong criterion (PVS1) and one moderate criterion (PM2) satisfy the Likely Pathogenic threshold under generic ACMG/AMP 2015 rules (1 Very Strong + 1 Moderate).3
DNMT3A
Final classification
Likely Pathogenic
DNMT3A c.1154del · p.Pro385ArgfsTer22
DNMT3A
PVS1 (very strong): NM_022552.4:c.1154delC is a frameshift deletion introducing a premature termination codon at position 406 (NP_072046.2:p.Pro385ArgfsTer22) in exon 10 of 22 coding exons, predicted to trigger nonsense-mediated decay. DNMT3A loss of function is an established disease mechanism for Tatton-Brown-Rahman syndrome, with a ClinGen haploinsufficiency score of 3.
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 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
DNMT3A c.1154del
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
3
generic_acmg_combination_rules
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
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
Population frequency
Overall AF
6 / 1,613,666
0.00037%
Highest · Admixed American
0.0017%
Homozygotes
0
grpmax FAF
0.00012%
Allele frequency by ancestry — gnomAD v4.1
observed in 2 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| Admixed American | 1 / 60,010 | 0.0017% | 0 |
| European (non-Finnish) | 5 / 1,179,996 | 0.00042% | 0 |
| European (Finnish) | 0 / 63,688 | — | — |
| Amish | 0 / 912 | — | — |
| East Asian | 0 / 44,892 | — | — |
| Middle Eastern | 0 / 6,082 | — | — |
| South Asian | 0 / 91,084 | — | — |
| Ashkenazi Jewish | 0 / 29,598 | — | — |
| African/African American | 0 / 74,918 | — | — |
“
This variant is present in gnomAD v4.1 (AF= 3.71824e-06; MAF= 0.00037%, 6/1613666 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66639e-05; MAF= 0.00167%, 1/60010 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
Overall AF
Not observed
Homozygotes
0
Not observed in any ancestry group across 8 populations in gnomAD v2.1.
“
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250600 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16144 alleles, homozygotes = 0).
“
This variant is absent from gnomAD-Canada.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
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.
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; COSV53048650, n = 6 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · 3 PMIDs triaged · 3 high-priority
3papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
21067377 ↗
functional
DNMT3A mutations in acute myeloid leukemia.
The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown. Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define
BS3PM1PS3
24614070 ↗
functional
Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.
Overgrowth disorders are a heterogeneous group of conditions characterized by increased growth parameters and other variable clinical features such as intellectual disability and facial dysmorphism. To identify new causes of human overgrowth, we performed exome sequencing in ten proband-parent trios and detected two de novo DNMT3A mutations. We identified 11 additional de novo mutations by sequenc
BS3PM1PS3
25964253 ↗
functional
Simpson's Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia.
To evaluate the impact of DNMT3A mutations on outcome in younger patients with cytogenetic intermediate-risk acute myeloid leukemia. Diagnostic samples from 914 patients (97% < 60 years old) were screened for mutations in DNMT3A exons 13 to 23. Clinical outcome was evaluated according to presence or absence of a mutation and stratified according to type of mutation (R882, non-R882 missense, or
BS3PM1PS3
Sources & reference links