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DNMT3Ac.1312dupLikely pathogenic
Print report
Variant interpretation report

DNMT3A c.1312dup, p.(Asp438GlyfsTer7)

NM_022552.4:c.1312dup NP_072046.2:p.(Asp438GlyfsTer7) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

Likely pathogenic.A likely pathogenic classification under the recorded framework.

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

This variant is a frameshift, NM_022552.4:c.1312dup, predicted to cause p.Asp438GlyfsTer7 (p.D438Gfs*7). Available gene-level evidence supports loss of function as an established DNMT3A disease mechanism, so a truncating variant of this type meets generic PVS1 criteria.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, with 0/1613462 alleles observed overall and 0/74884 alleles in the highest observed subpopulation. The observed population frequency is therefore below the non-VCEP PM2 threshold of 0.1%.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: 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.

02The sources

Evidence at a glance

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

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
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
Not assessed

No COSMIC evidence statement is recorded in this case.

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.

28 criteria with recorded statuses: 2 met · 4 not met · 13 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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

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.

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.

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.

Met · 2

PVS1 Very strongThis variant is a frameshift, NM_022552.4:c.1312dup, predicted to cause p.Asp438GlyfsTer7 (p.D438Gfs*7). Available gene-level evidence supports loss of function as an established DNMT3A disease mechanism, so a truncating variant of this type meets generic PVS1 criteria. Details ▾Hide ▴
Rule
Generic ACMG/AMP PVS1 using ClinGen SVI PVS1 framework fallback
Evidence considered
  • Predicted frameshift with premature termination
  • Generic PVS1 gene gate marked eligible for DNMT3A
  • Published germline DNMT3A syndrome literature supports loss of function
Still missing
  • Transcript-specific exon relevance and any rescue by alternative splicing were not independently confirmed beyond the available PVS1 materials.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗PMID:24614070 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, with 0/1613462 alleles observed overall and 0/74884 alleles in the highest observed subpopulation. The observed population frequency is therefore below the non-VCEP PM2 threshold of 0.1%. Details ▾Hide ▴
Rule
PM2_supporting by local non-VCEP frequency threshold
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 total AC 0 of AN 1613462
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 4 · evaluated, threshold not reached

PM1 Available hotspot review did not show this variant in a statistically significant hotspot or established critical region without benign variation. Details ▾Hide ▴
Evidence considered
  • No significant hotspot evidence at residue D438
Still missing
  • Domain-specific benign-variation assessment would be needed to revisit PM1
Sources
hotspots ↗
BA1 This variant does not meet BA1 because it is absent from gnomAD v2.1 and absent from gnomAD v4.1; the observed population frequency is 0, well below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Population AF 0
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant does not meet BS1 because it is absent from gnomAD v2.1 and absent from gnomAD v4.1; the observed population frequency is 0, below the 0.3% BS1 threshold used for non-VCEP review. Details ▾Hide ▴
Evidence considered
  • Population AF 0
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 Available population data do not show this variant in healthy adults at a frequency that would support BS2. No alleles and no homozygotes were observed in gnomAD v4.1. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 total AC 0 and homozygotes 0
Still missing
  • Independent healthy adult carrier observations with phenotype context
Sources
gnomad_v4 ↗

Not assessed · 13 · no assessment recorded

PS2 No confirmed de novo occurrence with verified maternity and paternity was available for this variant. Details ▾Hide ▴
Evidence considered
  • DNMT3A-related disorder is often de novo in published disease literature
  • No exact ClinVar record was available
Still missing
  • Proband-specific parental testing data
  • Phenotype details for any reported carrier
Sources
PMID:24614070 ↗clinvar ↗
PS3 Curated literature relevant to DNMT3A function was available, but no validated functional study for this exact variant was available to support or refute a damaging effect under PS3/BS3. Details ▾Hide ▴
Evidence considered
  • Curated literature gateway flagged functional relevance
  • No direct variant-specific assay result was available
Still missing
  • Variant-specific functional assay data
Sources
oncokb ↗PMID:21067377 ↗PMID:24614070 ↗PMID:25964253 ↗
PS4 No case-control enrichment data or multiple independent affected observations for this exact variant were available. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • Variant absent from gnomAD reference datasets
Still missing
  • Affected case counts for the exact variant
  • Formal enrichment or case-control data
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
PM6 No presumed de novo report without confirmed parentage was available for this variant. Details ▾Hide ▴
Evidence considered
  • DNMT3A disease background supports relevance of de novo data
  • No exact ClinVar record was available
Still missing
  • Variant-specific inheritance report with parental testing status
Sources
PMID:24614070 ↗clinvar ↗
PP1 No segregation data were available for this variant. Details ▾Hide ▴
Evidence considered
  • No family-level segregation evidence available
Still missing
  • Pedigree data
  • Affected and unaffected relative testing
PP4 No phenotype information was available to determine whether the clinical presentation is highly specific for a DNMT3A-related disorder. Details ▾Hide ▴
Evidence considered
  • No phenotype packet was available
Still missing
  • Detailed phenotype and clinical diagnosis
PP5 No external classified record from a qualifying reputable source was available for this exact variant. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Still missing
  • Reputable-source exact variant assertion
Sources
clinvar ↗
BS3 No well-established functional study showing a normal or benign effect for this exact variant was available. Details ▾Hide ▴
Evidence considered
  • Curated literature relevance without direct benign assay data
Still missing
  • Variant-specific benign functional data
Sources
oncokb ↗PMID:21067377 ↗PMID:24614070 ↗PMID:25964253 ↗
BS4 No non-segregation data were available for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation dataset available
Still missing
  • Family-level testing showing lack of segregation
BP2 No phase data with another pathogenic variant were available. Details ▾Hide ▴
Evidence considered
  • No second-variant phase data available
Still missing
  • Trans or cis phase information with another relevant variant
BP3 No evidence was available that this variant lies in a repetitive region without known function where small insertions or deletions are common. Details ▾Hide ▴
Evidence considered
  • No repeat-region evidence available
Still missing
  • Region-level repeat or low-complexity annotation
BP5 No alternate molecular explanation for the clinical findings was available. Details ▾Hide ▴
Evidence considered
  • No alternate-cause evidence available
Still missing
  • Comprehensive phenotype and alternate diagnosis data
BP6 No qualifying reputable-source benign classification was available for this exact variant. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Still missing
  • Reputable-source benign assertion
Sources
clinvar ↗
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to a different nucleotide change causing the same amino acid substitution. This variant is a frameshift and does not fit that rule. Details ▾Hide ▴
Evidence considered
  • Variant consequence is frameshift
PM3 N/APM3 is used for recessive disorders with trans observations. DNMT3A-related overgrowth syndrome is an autosomal dominant condition, so PM3 does not apply. Details ▾Hide ▴
Evidence considered
  • Published DNMT3A germline disease mechanism is dominant
Sources
PMID:24614070 ↗
PM4 N/APM4 is intended for protein length changes from in-frame insertions/deletions or stop-loss variants. This variant is a frameshift already captured by PVS1 logic. Details ▾Hide ▴
Evidence considered
  • Frameshift consequence
Sources
pvs1_variant_assessment
PM5 N/AClassic PM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change has been established. This variant is a frameshift, and available PM5 review did not support classic same-residue PM5 use. Details ▾Hide ▴
Evidence considered
  • PM5 candidate review marked classic PM5 semantics not safely applicable
  • Frameshift consequence
Sources
pm5_candidates
PP2 N/APP2 is a missense-specific rule and does not apply to this frameshift variant. Details ▾Hide ▴
Evidence considered
  • Frameshift consequence
PP3 N/AAvailable computational evidence does not provide an additional pathogenic prediction beyond the established frameshift consequence. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.06, and REVEL/BayesDel are not applicable to this duplication. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.06
  • Missense-specific predictors not applicable to a duplication
Sources
spliceai ↗
BP1 N/ABP1 is a missense-specific rule and does not apply to this frameshift variant. Details ▾Hide ▴
Evidence considered
  • Frameshift consequence
BP4 N/ASpliceAI predicts no significant splice impact, with a maximum delta score of 0.06, but BP4 does not offset the established truncating consequence of this frameshift variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.06
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous or certain noncoding variants and does not apply to this frameshift variant. Details ▾Hide ▴
Evidence considered
  • Frameshift consequence

Identifiers

Gene
DNMT3A
Transcript
NM_022552.4
Coding (HGVS c.)
NM_022552.4:c.1312dup
Protein (HGVS p.)
NP_072046.2:p.(Asp438GlyfsTer7)
GRCh38
chr2:25246276 T>TC
GRCh37
chr2:25469145 T>TC

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 0 / 1,613,462 alleles AF 0 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,613,462 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/AAvailable computational evidence does not provide an additional pathogenic prediction beyond the established frameshift consequence. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.06, and REVEL/BayesDel are not applicable to this duplication. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.06
  • Missense-specific predictors not applicable to a duplication
Sources
spliceai ↗
BP4 N/ASpliceAI predicts no significant splice impact, with a maximum delta score of 0.06, but BP4 does not offset the established truncating consequence of this frameshift variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.06
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous or certain noncoding variants and does not apply to this frameshift variant. Details ▾Hide ▴
Evidence considered
  • Frameshift consequence

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 0 / 1,613,462 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record 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

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).

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).

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 not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.