DNMT3A c.2638A>G, p.Met880Val
NM_022552.4:c.2638A>G
COSMIC ID: COSM120499
Likely Pathogenic
This DNMT3A c.2638A>G (p.M880V) variant is classified as Likely Pathogenic based on strong functional evidence (PS3), moderate rarity evidence (PM2), and supporting computational predictions (PP3).
ACMG/AMP Criteria Applied
PS3
PM2
PP3
Genetic Information
Gene & Transcript Details
Gene
DNMT3A
Transcript
NM_022552.5
MANE Select
Total Exons
23
Strand
Reverse (−)
Reference Sequence
NC_000002.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_022552.4 | RefSeq Select | 23 exons | Reverse |
| NM_022552.3 | Alternative | 23 exons | Reverse |
Variant Details
HGVS Notation
NM_022552.4:c.2638A>G
Protein Change
M880V
Location
Exon 23
(Exon 23 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 880 in gene DNMT3A
Alternate Identifiers
COSM120499
Variant interpretation based on transcript NM_022552.5
Genome Browser
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HGVS InputNM_022552:c.2638A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
European (non-Finnish)
0.00088%
Very Rare
Global: 0.000398%
European (non-Finnish): 0.00088%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251284Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251284 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00088%, 1/113694 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 880 in gene DNMT3A
Functional Summary
The DNMT3A M880V variant has been functionally characterized and demonstrates a damaging effect. In vitro studies show that this variant results in decreased methyltransferase activity compared to the wild-type protein, indicating a loss of DNMT3A function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.895
0.895
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Unknown
PP3 Applied
Yes
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence for this variant shows: M880V is a missense change and not a null variant. Therefore, this criterion is not applied because the variant type does not meet the rule.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: no other pathogenic variant at amino acid position M880 is described. Therefore, this criterion is not applied because there is no known pathogenic variant producing the same amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: no data on de novo status is available. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: in vitro studies demonstrate that M880V results in decreased DNMT3A methyltransferase activity compared to wild type, indicating loss of function. Therefore, this criterion is applied at Strong strength because well-established functional studies show a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence of the variant in affected individuals is significantly increased compared with controls'. The evidence for this variant shows: no case-control or cohort data demonstrating increased prevalence in affected individuals. Therefore, this criterion is not applied due to lack of prevalence data.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or critical and well‐established functional domain without benign variation'. The evidence for this variant shows: no specific data defining M880 as a mutational hot spot or uniquely critical domain in DNMT3A. Therefore, this criterion is not applied due to insufficient evidence of a hot spot or critical domain designation.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: observed in gnomAD at MAF=0.000398%, with no homozygotes, below thresholds for benign frequency. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for a recessive disorder'. The evidence for this variant shows: no data regarding trans configuration with another variant. Therefore, this criterion is not applied due to lack of trans-phase data.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes as a result of in‐frame deletions/insertions in a non‐repeat region or stop‐loss variants'. The evidence for this variant shows: M880V is a single amino acid substitution without length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before'. The evidence for this variant shows: no other pathogenic variant reported at residue M880. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo information is available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co‐segregation with disease in multiple affected family members in a gene definitively known to cause the disease'. The evidence for this variant shows: no familial segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: DNMT3A has both truncating and missense pathogenic variants; missense is not exclusively common and benign missense rate is unclear. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product'. The evidence for this variant shows: REVEL score of 0.90 exceeds the 0.75 threshold; SpliceAI score low but does not detract from missense deleterious prediction. Therefore, this criterion is applied at Supporting strength due to strong in silico pathogenicity predictions.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no phenotype or family history data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: not reported in ClinVar or other public databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for disorder'. The evidence for this variant shows: frequency is well below thresholds for common benign variants. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for disorder'. The evidence for this variant shows: frequency is low and not greater than expected. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: no healthy individual data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene for which primarily truncating variants are known to cause disease'. The evidence for this variant shows: DNMT3A has known pathogenic missense variants (e.g., R882H). Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in any inheritance pattern'. The evidence for this variant shows: no data on cis/trans configuration with other variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In‐frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: this is a missense substitution, not an in‐frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence for this variant shows: computational tools predict deleterious effect (REVEL 0.90). Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no alternate molecular diagnosis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without available evidence'. The evidence for this variant shows: no benign reports found. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing and no amino acid change'. The evidence for this variant shows: M880V is a missense change. Therefore, this criterion is not applied.