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
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.04 | 85 bp |
| Donor Loss (DL) | 0.74 | 0 bp |
| Acceptor Gain (AG) | 0.01 | 383 bp |
| Donor Gain (DG) | 0.33 | 10 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 is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion)." The evidence for this variant shows: it is a missense change (R803K), not a null variant. Therefore, this criterion is not applied because the variant does not meet the null variant requirement.
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 report of R803K as a pathogenic change in DNMT3A. Therefore, PS1 is not applied due to lack of a previously established pathogenic 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 data on de novo occurrence or parental testing. Therefore, PS2 is not applied due to absence of de novo confirmation.
PS3 (Not Applied)
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 characterization of R803K. Therefore, PS3 is not applied because functional studies are lacking.
PS4 (Not Applied)
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. Therefore, PS4 is not applied due to absence of prevalence data in affected individuals.
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: R803K is in the methyltransferase domain, but no specific hotspot annotation or lack of benign variation has been established. Therefore, PM1 is not applied.
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: MAF = 0.00119% in gnomAD, extremely rare. Therefore, PM2 is applied at Moderate strength because the allele frequency is well below thresholds in controls.
PM3 (Not Applied)
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: no data on trans-inheritance or compound heterozygosity. Therefore, PM3 is not applied due to lack of trans-segregation data.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: it is a missense substitution without length change. Therefore, PM4 is not applied.
PM5 (Moderate)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen." The evidence for this variant shows: R803K is a novel missense at a residue with at least one other pathogenic missense reported. Therefore, PM5 is applied at Moderate strength.
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 or parental data. Therefore, PM6 is 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 analysis. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism of disease." The evidence for this variant shows: DNMT3A has both LoF and missense mechanisms, but rate of benign variation is not well established. Therefore, PP2 is not applied.
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: SpliceAI predicts a donor loss score of 0.74 and in silico meta-predictors support possible impact. Therefore, PP3 is applied at Supporting strength.
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, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without accessible evidence." The evidence for this variant shows: no such reports. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (>5%)." The evidence for this variant shows: MAF = 0.00119%, well below threshold. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder." The evidence for this variant shows: MAF is very low. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy adult individuals for a dominant disorder with expected full penetrance at an early age." The evidence for this variant shows: no healthy adult screening data. Therefore, BS2 is 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: no functional studies available. Therefore, BS3 is not applied.
BS4 (Not Applied)
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, BS4 is 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." The evidence for this variant shows: missense and truncating mechanisms both reported for DNMT3A. Therefore, BP1 is not applied.
BP2 (Not Applied)
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 such observations. Therefore, BP2 is 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 missense variant. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact." The evidence for this variant shows: in silico predictions are mixed with some supporting deleterious effect. Therefore, BP4 is not applied.
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 such cases reported. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without accessible evidence." The evidence for this variant shows: no such reports. Therefore, BP6 is 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 non-synonymous. Therefore, BP7 is not applied.