DNMT3A c.2305A>G, p.Ile769Val
NM_022552.4:c.2305A>G
Variant of Uncertain Significance (VUS)
The variant c.2305A>G (p.I769V) in DNMT3A is classified as VUS based on PM2 (absent from controls), PM5 (novel missense at a residue with known pathogenic variant), and PP3 (supporting computational evidence). Insufficient additional evidence is available to reach a pathogenic or benign classification.
ACMG/AMP Criteria Applied
PM2
PM5
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.2305A>G
Protein Change
I769V
Location
Exon 19
(Exon 19 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 769 in gene DNMT3A
Variant interpretation based on transcript NM_022552.5
Genome Browser
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HGVS InputNM_022552:c.2305A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
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 769 in gene DNMT3A
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.79
0.79
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 4.70primateai: T
Neutral: Show all
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: the variant is a missense change (c.2305A>G; p.I769V), not a null variant. Therefore, this criterion is not applied because the variant is not a null variant.
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 previously established pathogenic variant results in p.I769V. Therefore, this criterion is not applied because there is no known pathogenic variant with 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 de novo data available (parental testing not performed). Therefore, this criterion is not applied because de novo status with confirmed parental origin is not available.
PS3
PS3 (Not Applied) Strength Modified
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: no functional studies have been performed for DNMT3A I769V. Therefore, this criterion is not applied because functional data are lacking.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no case-control or prevalence data. Therefore, this criterion is not applied because case-control data are unavailable.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: p.I769 is not known to reside within a defined mutational hot spot or critical functional domain. Therefore, this criterion is not applied due to lack of hotspot/domain evidence.
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: the variant is not found in gnomAD, ExAC, or 1000 Genomes. Therefore, this criterion is applied at Moderate strength because the variant is absent from large 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 recessive disorders)'. The evidence for this variant shows: DNMT3A-associated conditions are autosomal dominant and no trans observations are relevant. Therefore, this criterion is not applied because the gene's disease mechanism and inheritance do not support PM3.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: it is a missense change with no protein length alteration. Therefore, this criterion is not applied because the variant does not alter protein length.
PM5
PM5 (Moderate)
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'. The evidence for this variant shows: another missense variant at residue I769 has been reported as pathogenic. Therefore, this criterion is applied at Moderate strength because p.I769 is a residue with established pathogenic missense variation.
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: de novo status was not assessed or assumed. Therefore, this criterion is not applied due to lack of de novo assumption.
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'. The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied because familial segregation information is unavailable.
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: while DNMT3A harbors disease-associated missense variants, gene-specific benign missense constraint metrics are insufficient. Therefore, this criterion is not applied due to lack of gene-specific missense constraint data.
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/gene product (e.g., conservation, splicing impact)'. The evidence for this variant shows: REVEL score = 0.79 (>0.75 threshold), PolyPhen-2: probably damaging, MetaSVM: D, MetaLR: D. Therefore, this criterion is applied at Supporting strength because multiple in silico tools predict a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no detailed patient phenotype provided. Therefore, this criterion is not applied because phenotype specificity data are missing.
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: no entries in ClinVar or other reputable sources. Therefore, this criterion is not applied because no external pathogenic reports are available.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder (based on population data)'. The evidence for this variant shows: allele frequency = 0% in population databases. Therefore, this criterion is not applied because the frequency is not high.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: allele frequency = 0% in population databases. Therefore, this criterion is not applied because the frequency does not exceed disorder expectations.
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 data from healthy adult individuals. Therefore, this criterion is not applied due to lack of healthy individual observations.
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: no functional studies performed. Therefore, this criterion is not applied because functional data are lacking.
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 analysis reported. Therefore, this criterion is not applied because segregation data are unavailable.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: DNMT3A disease mechanism includes pathogenic missense variants. Therefore, this criterion is not applied because missense variants are a known mechanism.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows: no observations of cis/trans occurrence with other variants. Therefore, this criterion is not applied because no such observations are available.
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: it is a missense change, not an in-frame indel. Therefore, this criterion is not applied because variant type does not match.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact'. The evidence for this variant shows: computational tools mostly predict deleterious effect. Therefore, this criterion is not applied because in silico evidence does not support benign impact.
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 basis reported. Therefore, this criterion is not applied because no alternate cause is identified.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: no reputable benign reports. Therefore, this criterion is not applied because no such reports exist.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied because it is not a synonymous variant.