Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_022552.4 | RefSeq Select | 4324 nt | 268–3006 |
| NM_022552.5 | MANE Select | 9421 nt | 278–3016 |
| NM_022552.3 | Alternative | 4314 nt | 258–2996 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The DNMT3A G706R variant has been functionally characterized and shown to result in decreased protein stability and reduced methyltransferase activity in vitro. These findings indicate that the variant is inactivating and likely leads to a loss of DNMT3A protein function.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.04 | 64 bp |
| Donor Loss (DL) | 0.0 | -61 bp |
| Acceptor Gain (AG) | 0.01 | 33 bp |
| Donor Gain (DG) | 0.0 | -57 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
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: it is a missense change (G706R), not a null variant. Therefore, this criterion is not applied at Not Applied because the variant type does not meet the rule.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". The evidence for this variant shows: no prior pathogenic variant altering glycine at position 706 has been reported. Therefore, this criterion is not applied at Not Applied because there is no known pathogenic variant with the same amino acid change.
PS2 (Not Applied)
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 are available. Therefore, this criterion is not applied at Not Applied due to lack of de novo confirmation.
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 decreased DNMT3A protein stability and reduced methyltransferase activity for G706R. Therefore, this criterion is applied at Strong strength because the functional data clearly support a damaging effect.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared with controls". The evidence for this variant shows: no case‐control or case series data demonstrating enrichment in affected individuals. Therefore, this criterion is not applied at Not Applied due to absence of frequency data in cases.
PM1 (Not Applied)
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: location at residue 706 is not documented as a mutational hotspot or within a defined critical domain. Therefore, this criterion is not applied at Not Applied for lack of hotspot/domain evidence.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in population databases". The evidence for this variant shows: G706R is not found in gnomAD or other large population cohorts (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant". The evidence for this variant shows: DNMT3A‐related disease is typically autosomal dominant and no trans data are available. Therefore, this criterion is not applied at Not Applied.
PM4 (Not Applied)
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 substitution without length change. Therefore, this criterion is not applied at Not Applied.
PM5 (Not Applied)
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 missense substitutions at residue 706 are documented. Therefore, this criterion is not applied at Not Applied.
PM6 (Not Applied)
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 parental testing data. Therefore, this criterion is not applied at Not Applied.
PP1 (Not Applied)
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 are available. Therefore, this criterion is not applied at Not Applied.
PP2 (Not Applied)
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: insufficient data on DNMT3A’s benign missense rate and mechanism specificity. Therefore, this criterion is not applied at Not Applied.
PP3 (Not Applied)
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: in silico predictions are mixed and SpliceAI predicts minimal splicing impact. Therefore, this criterion is not applied at Not Applied due to conflicting computational results.
PP4 (Not Applied)
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 provided. Therefore, this criterion is not applied at Not Applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports the variant as pathogenic, but without accessible evidence". The evidence for this variant shows: not reported in ClinVar or other curated databases. Therefore, this criterion is not applied at Not Applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is greater than expected for disorder (stand‐alone benign)". The evidence for this variant shows: MAF=0% in controls. Therefore, this criterion is not applied at Not Applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder (strong benign)". The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied at Not Applied.
BS2 (Not Applied)
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 at Not Applied.
BS3 (Not Applied)
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 at Not Applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss‐of‐function causes disease (supporting benign)". The evidence for this variant shows: DNMT3A pathogenic mechanism includes loss‐of‐function, but missense can be pathogenic. Therefore, this criterion is not applied at Not Applied.
BP2 (Not Applied)
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". The evidence for this variant shows: no phasing data. Therefore, this criterion is not applied at Not Applied.
BP3 (Not Applied)
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 single‐amino‐acid substitution, not an in‐frame indel. Therefore, this criterion is not applied at Not Applied.
BP4 (Supporting)
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: mixed in silico results with SpliceAI score 0.04 indicating no splice impact and overall benign computational profile. Therefore, this criterion is applied at Supporting strength because computational data lean benign.
BP5 (Not Applied)
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 at Not Applied.
BP6 (Not Applied)
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 such reports exist. Therefore, this criterion is not applied at Not Applied.
BP7 (Not Applied)
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, not synonymous. Therefore, this criterion is not applied at Not Applied.