Starting
Initialising…
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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
DNMT3A
Transcript
NM_022552.4
HGVS · transcript:coding
NM_022552.4:c.1154del
Consequence
N/A
GRCh38
chr2:25246744 CG>C
GRCh37
chr2:25469613 CG>C
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 moderate; combination = 1 very strong + 1 moderate, 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 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2 Likely Pathogenic
DNMT3A c.1154del

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

PVS1 + PM2 → Likely Pathogenic
1 pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
2 gnomad_v2 ↗gnomad_v4 ↗
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 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      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.
      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).
      🇨🇦 CA
      This variant is absent from gnomAD-Canada.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.00037% · 6 / 1,613,666
      0 hom · FAF 0.00012%
      Admixed American
      1 / 60,010
      0.0017%
      European (non-Finnish)
      5 / 1,179,996
      0.00042%
      + 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
      gnomAD v2.1
      Absent · 0 / 250,600
      0 hom
      Not observed in any ancestry group.
      + 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
      ClinVar screenshot
      ClinVar
      This variant is absent from ClinVar.
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
      SpliceAI ↗
      Functional / OncoKB screenshot
      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 screenshot
      COSMIC
      Cancer hotspots screenshot
      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.
      COSMIC ↗ Hotspots ↗
      Sources & reference links
      7Sources
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      Triaged references · 3 PMIDs not cited in assessment
      21067377 ↗ DNMT3A mutations in acute myeloid leukemia. ONCOKB
      24614070 ↗ Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. ONCOKB
      25964253 ↗ Simpson's Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia. ONCOKB