Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_003620.2 | Alternative | 3163 nt | 223–2040 |
| NM_003620.4 | MANE Select | 4768 nt | 223–2040 |
| NM_003620.3 | RefSeq Select | 4790 nt | 233–2050 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Likely benign (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 146 bp |
| Donor Loss (DL) | 0.0 | -16 bp |
| Acceptor Gain (AG) | 0.0 | -72 bp |
| Donor Gain (DG) | 0.0 | -207 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: it is a missense change (F445I), not a null variant. Therefore, this criterion is not applied.
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 known pathogenic variant causing the same F445I change has been reported. Therefore, this criterion is not applied.
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. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies show a damaging effect on the gene or gene product." The evidence for this variant shows: no functional characterization studies are available. Therefore, this criterion is not applied.
PS4 (Not Applied)
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 data demonstrating increased prevalence in affected individuals. Therefore, this criterion is not applied.
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: no specific hotspot or functional domain annotation provided. Therefore, this criterion 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: it is not found in gnomAD, 1000 Genomes, or ExAC. Therefore, this criterion is applied at Moderate strength because the variant is absent from population 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: no information on trans phase with any pathogenic variant. Therefore, this criterion is 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 change without alteration of protein length. Therefore, this criterion is 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 missense change determined to be pathogenic has been seen before." The evidence for this variant shows: no known pathogenic missense change at codon 445. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." The evidence for this variant shows: no data on de novo status. Therefore, this criterion 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 data available. Therefore, this criterion is 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 missense constraint or mechanism for PPM1D. Therefore, this criterion is 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/gene product." The evidence for this variant shows: computational tools (REVEL 0.07, CADD, SIFT, PolyPhen-2, SpliceAI) predict no impact. Therefore, this criterion is not applied.
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.
PP5 (Not Applied)
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 reputable source reports it as pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for disorder." The evidence for this variant shows: allele frequency is 0% in gnomAD. Therefore, this criterion 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: allele frequency is 0% in gnomAD. Therefore, this criterion is 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 observations in healthy cohort. Therefore, this criterion 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, this criterion 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 analysis performed. Therefore, this criterion 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: mechanism of PPM1D disease is not solely loss-of-function. Therefore, this criterion is 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 data on phase with other variants. Therefore, this criterion 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 change, not an indel. Therefore, this criterion is 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 (conservation, evolutionary, splicing impact, etc.)." The evidence for this variant shows: REVEL score 0.07 (below threshold 0.15), CADD, SIFT, PolyPhen-2, MetaSVM, MetaLR, PrimateAI, DEOGEN2 predict benign effect, and SpliceAI scores indicate no splicing impact. Therefore, this criterion is applied at Supporting strength due to concordant benign computational predictions.
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 case information available. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: ClinVar lists it as Likely benign (1 submission). Therefore, this criterion is applied at Supporting strength.
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.