Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_003620.3 | RefSeq Select | 4790 nt | 233–2050 |
| NM_003620.4 | MANE Select | 4768 nt | 223–2040 |
| NM_003620.2 | Alternative | 3163 nt | 223–2040 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PPM1D A481Pfs*2 variant is functionally characterized as a truncating mutation that confers gain-of-function activity. This variant results in a C-terminally truncated version of the PPM1D protein, which negatively regulates proteins such as TP53 by dephosphorylation. Functional studies demonstrate that PPM1D truncating mutations, including similar variants, lead to increased protein stability, attenuated activation of DNA damage response mediators, and enhanced cell growth and colony formation. In vivo mouse models show that these mutations are activating, as evidenced by increased development of acute myeloid leukemia following ionizing radiation exposure. Additionally, PPM1D truncating mutations confer resistance to chemotherapeutic agents but are sensitive to specific small molecule inhibitors. Overall, the functional evidence supports a damaging, oncogenic effect of the PPM1D A481Pfs*2 variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -176 bp |
| Donor Loss (DL) | 0.0 | -311 bp |
| Acceptor Gain (AG) | 0.0 | -167 bp |
| Donor Gain (DG) | 0.0 | -120 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, etc.) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows that PPM1D truncating variants confer a gain‐of‐function effect rather than loss of function. Therefore, this criterion is not applied because loss of function is not the disease mechanism for PPM1D.
PS1 (Not Applied)
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 previous report of the same amino acid change via a different nucleotide change. 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." There are no data on de novo status for this variant. Therefore, this criterion is not applied.
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "Well‐established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows that PPM1D A481Pfs*2 yields a C‐terminally truncated protein with increased stability and oncogenic gain‐of‐function, with in vitro and in vivo studies demonstrating enhanced cell growth, leukemia development in mice, and altered DNA damage response. Therefore, this criterion is applied at Strong strength because these well‐established functional studies support a damaging effect.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls." There are no case‐control or cohort data demonstrating increased frequency 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 or well‐established functional domain without benign variation." There is no evidence this frameshift lies in a recognized hotspot separate from the general C‐terminal truncation region. 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)." The evidence for this variant shows an extremely low allele frequency (MAF=0.000398% in gnomAD) with no homozygotes. Therefore, this criterion is applied at Moderate strength because the variant is absent or extremely rare in population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)." This variant is associated with a dominant cancer predisposition and there are no data on compound heterozygosity. 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." This variant is a frameshift leading to truncation, which is typically evaluated under PVS1 (not applicable here). Therefore, PM4 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 pathogenic missense change has been seen." This is a frameshift, not a missense change. Therefore, this criterion is 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." There are no data regarding de novo occurrence. 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." No segregation data are 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." This is a frameshift variant and not a missense change. 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." Computational predictions show no deleterious splicing impact and no pathogenic in silico predictions. 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 highly specific for a disease with a single genetic etiology." No phenotype or family history data are 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 variant is not reported in ClinVar or other reputable sources. 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 the disorder." The allele frequency is extremely low. 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 the disorder." The frequency remains below disease‐relevant thresholds. 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." No such observations are reported. 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." Functional studies show a damaging gain‐of‐function effect. 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." No segregation data are available. 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." This is a truncating variant. 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 dominant disorders or in cis with a pathogenic variant." No such observations are reported. 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." This is a frameshift variant. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact." Computational tools do not predict a splicing change but this criterion is reserved for missense or splicing predictions. Therefore, it 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." No such case data are available. Therefore, this criterion is 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." No such reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing." This is not a synonymous variant. Therefore, this criterion is not applied.