0%
DNMT3Ac.1256delUncertain significance
Print report
Variant interpretation report

DNMT3A c.1256del, p.(Pro419LeufsTer232)

NM_022552.4:c.1256del NP_072046.2:p.(Pro419LeufsTer232) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About DNMT3A

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

NM_022552.4:c.1256del is a frameshift deletion in exon 10 of 23, predicted to introduce a premature termination codon at p.Pro419LeufsTer232 with consequent nonsense-mediated decay. DNMT3A loss of function is an established mechanism for Tatton-Brown-Rahman syndrome (DNMT3A overgrowth syndrome), a germline overgrowth disorder. Under ClinGen SVI PVS1 recommendations (PMC6185798), this frameshift variant meets PVS1 at full strength.

PM2Supporting
PM2 · supporting

NM_022552.4:c.1256del is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (HostSeq genomes). Under generic ACMG/AMP, absence from large population databases in a gene where LoF variants are not commonly observed in controls supports PM2 at supporting level.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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 VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV106054743, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 19 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_022552.4:c.1256del (p.Pro419LeufsTer232) is a frameshift deletion in exon 10 of DNMT3A, predicted to cause nonsense-mediated decay and complete loss of protein function. DNMT3A loss of function is an established mechanism for Tatton-Brown-Rahman syndrome (DNMT3A overgrowth syndrome), a germline disorder characterized by overgrowth, intellectual disability, and facial dysmorphism.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, supporting rarity in the general population.

No variant-specific functional studies, de novo reports, case-control data, or segregation analyses were identified in the reviewed literature for this specific variant. A single ClinVar submission from a clinical laboratory classifies the variant as Likely pathogenic for Tatton-Brown-Rahman overgrowth syndrome, but the evidence trail is limited to guideline citations without variant-specific published data.

Under generic ACMG/AMP 2015 criteria, the combination of PVS1 (very_strong) and PM2 (supporting) is insufficient to reach a Likely Pathogenic classification, which requires at minimum 1 Very Strong + 1 Moderate or 1 Strong + 1-2 Moderate or 2 Moderate + 2 Supporting criteria. The classification falls into Variant of Uncertain Significance (VUS), favoring pathogenic, pending additional clinical or functional evidence.

Met · 2

PVS1 Very strongNM_022552.4:c.1256del is a frameshift deletion in exon 10 of 23, predicted to introduce a premature termination codon at p.Pro419LeufsTer232 with consequent nonsense-mediated decay. DNMT3A loss of function is an established mechanism for Tatton-Brown-Rahman syndrome (DNMT3A overgrowth syndrome), a germline overgrowth disorder. Under ClinGen SVI PVS1 recommendations (PMC6185798), this frameshift variant meets PVS1 at full strength. Details ▾Hide ▴
Evidence considered
  • Frameshift variant in exon 10/23 introducing PTC at codon 419 with predicted NMD
  • DNMT3A germline loss of function is an established disease mechanism for Tatton-Brown-Rahman syndrome (PMID:24614070
  • PMID:37160317
  • PMID:38937076)
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 SupportingNM_022552.4:c.1256del is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (HostSeq genomes). Under generic ACMG/AMP, absence from large population databases in a gene where LoF variants are not commonly observed in controls supports PM2 at supporting level. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • Absent from gnomAD v4.1 (0 alleles)
  • Absent from gnomAD-Canada v1.0 (0 alleles)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 19 · evaluated, threshold not reached

PS2 No de novo occurrence of NM_022552.4:c.1256del was identified in any reviewed publication. While de novo DNMT3A mutations are documented in Tatton-Brown-Rahman syndrome (PMID:24614070), this specific variant was not among the reported de novo events. Details ▾Hide ▴
Still missing
  • No de novo report available for this specific variant
PS3 No variant-specific functional studies for NM_022552.4:c.1256del were identified in the reviewed literature. OncoKB curation suggests likely loss-of-function as a biological effect, but this is a curated inference rather than direct experimental evidence for this variant. Details ▾Hide ▴
Still missing
  • No variant-specific functional assays available
PS4 No case-control or prevalence data are available to demonstrate that this variant is significantly enriched in affected individuals compared with controls. The variant is absent from gnomAD population databases, but the number of independent proband observations is insufficient to meet PS4 thresholds. Details ▾Hide ▴
Still missing
  • No proband count or case-control data
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PM1 NM_022552.4:c.1256del is located in exon 10, which lies between the PWWP domain (exons 8-9) and the ADD domain (exons 13-15) of DNMT3A. Cancer Hotspots analysis did not identify this position as a statistically significant mutational hotspot. No well-established critical functional domain has been specifically defined at this residue under generic ACMG criteria. Details ▾Hide ▴

No further detail was recorded.

PM6 No assumed de novo report was identified for NM_022552.4:c.1256del in any reviewed publication. PM6 requires at least one report of the variant occurring de novo without confirmed paternity/maternity. Details ▾Hide ▴
Still missing
  • No de novo observation reported
PP1 No cosegregation data are available for NM_022552.4:c.1256del in affected families. PP1 requires evidence of segregation with disease in multiple affected family members. Details ▾Hide ▴
Still missing
  • No segregation data available
PP3 SpliceAI predicts no significant splice impact (max delta score 0.03, well below the 0.2 threshold). REVEL and BayesDel are not applicable to non-SNV variants. HCI prior scores are not available for DNMT3A. No in silico tool provides evidence that an effect beyond what PVS1 already captures is present. Under PMC6185798 guidance, PP3 should not be stacked with PVS1 for the same predicted effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.03 (no predicted splice impact)
Sources
spliceai ↗
PP4 No patient phenotype or family history data are available for individuals carrying NM_022552.4:c.1256del. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
  • No patient phenotype data available
PP5 PP5 requires a reputable source to have reported the variant as pathogenic with evidence not available for independent evaluation. While a ClinVar submission from CHRU Nancy classifies this variant as Likely pathogenic, the record is mapped to a different transcript version (NM_022552.5:c.1925del), and the evidence trail cites only the ACMG guidelines (PMID:25741868) without variant-specific published evidence. A single clinical laboratory submission without expert panel validation does not constitute a reputable source under PP5. Details ▾Hide ▴
Still missing
  • No validated evidence trail from the ClinVar submitter
Sources
clinvar ↗
BA1 NM_022552.4:c.1256del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, with an allele frequency of 0. The BA1 threshold of >5% is not met. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0.0 in all population databases
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 NM_022552.4:c.1256del is absent from all population databases. The BS1 threshold of >0.3% allele frequency (generic ACMG non-VCEP) is not met. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0.0 in all population databases
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No observations of NM_022552.4:c.1256del in healthy adults for a recessive condition or in trans with a pathogenic variant for a dominant condition are available. Details ▾Hide ▴

No further detail was recorded.

BS3 No well-established functional studies demonstrating no damaging effect of NM_022552.4:c.1256del were identified. No variant-specific functional data of any kind are available for this variant. Details ▾Hide ▴
Still missing
  • No functional studies available for this variant
BS4 No segregation data are available for NM_022552.4:c.1256del. BS4 requires lack of segregation in affected family members, which cannot be assessed without family studies. Details ▾Hide ▴
Still missing
  • No segregation data available
BP2 No observation of NM_022552.4:c.1256del in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant is available. Details ▾Hide ▴

No further detail was recorded.

BP4 SpliceAI predicts no significant splice impact (max delta 0.03). However, SpliceAI alone does not constitute 'multiple lines of computational evidence' suggesting no impact, and for frameshift variants the primary deleterious mechanism is protein truncation with NMD — an effect not assessed by in silico splicing or missense prediction tools. BP4 is therefore not met. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.03 (no predicted splice impact)
Sources
spliceai ↗
BP5 No observation of NM_022552.4:c.1256del in an individual with an alternate molecular basis for disease has been reported. Details ▾Hide ▴

No further detail was recorded.

BP6 No reputable source has reported NM_022552.4:c.1256del as benign. The only ClinVar record classifies it as Likely pathogenic. Details ▾Hide ▴

No further detail was recorded.

PS5 A single ClinVar submission (SCV004805237, Clinical Genetics Laboratory, CHRU Nancy) classifies a matching variant as Likely pathogenic for Tatton-Brown-Rahman overgrowth syndrome, but this is a single-submitter record with no expert panel validation and the record is mapped to a different transcript version (NM_022552.5:c.1925del). Under generic ACMG, a single clinical laboratory submission without published evidence does not meet the PS5 threshold requiring a reputable source. Details ▾Hide ▴
Still missing
  • ClinVar record not from an expert panel
  • no published evidence trail
Sources
clinvar ↗
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies when a variant produces the same amino acid change as a known pathogenic missense variant. NM_022552.4:c.1256del is a frameshift variant, not a missense substitution, and therefore PS1 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASKIP: trivially not applicable per adjudication instructions. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. NM_022552.4:c.1256del is a frameshift deletion causing a premature termination codon (p.Pro419LeufsTer232), not an in-frame change. The protein-length-altering effect is captured by PVS1. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to a novel missense variant at an amino acid residue where a different pathogenic missense change has been documented. NM_022552.4:c.1256del is a frameshift variant, not a missense substitution. Automatic PM5 candidate harvesting was unable to identify same-residue missense comparators. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes where missense variants are a common disease mechanism and benign missense variation is rare. DNMT3A disease is driven primarily by loss-of-function variants, and NM_022552.4:c.1256del is a frameshift variant, not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. NM_022552.4:c.1256del is itself a truncating (frameshift) variant, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without known function. NM_022552.4:c.1256del is a frameshift variant, not an in-frame change. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and non-conserved nucleotide. NM_022552.4:c.1256del is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
DNMT3A
Transcript
NM_022552.4
Coding (HGVS c.)
NM_022552.4:c.1256del
Protein (HGVS p.)
NP_072046.2:p.(Pro419LeufsTer232)
GRCh38
chr2:25246642 AG>A
GRCh37
chr2:25469511 AG>A
ClinVar
3064272
COSMIC
COSV106054743

Gene diagram

Every interpreted variant in DNMT3A, mapped onto the exon structure of NM_022552.4. Select a row to find it on the plot.

DNMT3ANM_022552.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +475 bp
0.010
SpliceAI acceptor gainat +174 bp
0.020
SpliceAI donor lossat -451 bp
0.000
SpliceAI donor gainat +57 bp
0.030
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SpliceAI predicts no significant splice impact (max delta score 0.03, well below the 0.2 threshold). REVEL and BayesDel are not applicable to non-SNV variants. HCI prior scores are not available for DNMT3A. No in silico tool provides evidence that an effect beyond what PVS1 already captures is present. Under PMC6185798 guidance, PP3 should not be stacked with PVS1 for the same predicted effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.03 (no predicted splice impact)
Sources
spliceai ↗
BP4 SpliceAI predicts no significant splice impact (max delta 0.03). However, SpliceAI alone does not constitute 'multiple lines of computational evidence' suggesting no impact, and for frameshift variants the primary deleterious mechanism is protein truncation with NMD — an effect not assessed by in silico splicing or missense prediction tools. BP4 is therefore not met. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.03 (no predicted splice impact)
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and non-conserved nucleotide. NM_022552.4:c.1256del is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

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

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • DNMT3A mutations in acute myeloid leukemia.
    Reports discovery of somatic DNMT3A mutations including a frameshift mutation in acute myeloid leukemia through whole-genome sequencing of an AML patient and targeted sequencing of 280 additional patients. NM_022552.4:c.1256del was not among the variants described.
    Does not name this variant
    PMID 21067377 ↗
  • Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.
    Identifies 13 de novo DNMT3A mutations in 152 individuals with overgrowth phenotypes, establishing DNMT3A as a cause of Tatton-Brown-Rahman syndrome (DNMT3A overgrowth syndrome). Specific mutations reported include p.Trp297del, p.Leu648Pro, and ten additional nonsynonymous mutations. NM_022552.4:c.1256del (p.Pro419LeufsTer232) was not among the mutations listed.
    Does not name this variant
    PMID 24614070 ↗
  • Simpson's Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia.
    Evaluates the prognostic impact of DNMT3A mutations in 914 younger adults with AML, screening exons 13-23 only. Reports 13 frameshift mutations within the screened region. NM_022552.4:c.1256del resides in exon 10, which was outside the screening scope of this study, and was not identified.
    Does not name this variant
    PMID 25964253 ↗
  • 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.
    ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a methodological reference describing the variant classification framework, not a study reporting specific variants. NM_022552.4:c.1256del is not mentioned.
    Does not name this variant
    PMID 25741868 ↗
  • Tatton-Brown-Rahman Syndrome.
    Adam MP et al. · 1993
    GeneReviews entry for Tatton-Brown-Rahman Syndrome summarizing the clinical characteristics, genetic basis, and management of TBRS. Full text and abstract were not available for review; variant-level confirmation of NM_022552.4:c.1256del could not be performed.
    Does not name this variant
    PMID 35771960 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.030 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is present in ClinVar (Variation ID: 3064272); submission details unavailable.

In silico

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

Functional

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

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV106054743, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.