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"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 | -128 bp |
| Donor Loss (DL) | 0.0 | 230 bp |
| Acceptor Gain (AG) | 0.0 | -346 bp |
| Donor Gain (DG) | 0.0 | -481 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "PVS1 – 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 (R536K), not a null variant. Therefore, this criterion is not applied because the variant type does not meet the definition of a null variant.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: there is no known pathogenic variant at the same amino acid (R536) in PPM1D. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no parental genotyping or de novo confirmation is available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: "PS3 – 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 on R536K in PPM1D. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "PS4 – Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or affected‐cohort data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "PM1 – Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: R536 is not reported as a mutational hotspot or within a known critical functional domain of PPM1D. Therefore, this criterion is not applied.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "PM2 – Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: it has a MAF of 0.00955% in gnomAD with no homozygotes, which is below the threshold for a rare dominant variant. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "PM3 – Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no data on trans configuration with a known pathogenic allele. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "PM4 – 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 in protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no pathogenic missense variants have been reported at residue R536. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "PM6 – Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "PP1 – Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation studies have been reported. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "PP2 – 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: PPM1D does not have established disease mechanism solely by missense variants. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: most in silico tools predict a benign effect and SpliceAI predicts no splicing impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "PP4 – Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype or clinical context provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "PP5 – Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: no reputable source has reported it as pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "BA1 – Allele frequency is too high for the disorder". The evidence for this variant shows: MAF (0.00955%) is well below the BA1 threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "BS1 – Allele frequency is greater than expected for the disorder". The evidence for this variant shows: MAF is low and not above expected allele frequency thresholds. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "BS2 – Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: no data on observation in healthy, phenotyped individuals. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "BS3 – Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "BS4 – Lack of segregation in affected family members". The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
BP1 (Supporting)
According to standard ACMG guidelines, the rule for BP1 is: "BP1 – Missense variant in a gene where only loss of function causes disease". The evidence for this variant shows: PPM1D disease mechanism is established for truncating (LoF) variants, not missense. Therefore, this criterion is applied at Supporting strength because the variant is a missense in a gene where only LoF is known to cause disease.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "BP2 – Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no data on cis/trans configuration with known pathogenic variants. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "BP3 – 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.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "BP4 – Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: multiple in silico predictors (CADD, PROVEAN, MetaSVM, etc.) predict a benign effect and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because there is consistent benign computational evidence.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "BP5 – Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no such case context is available. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "BP6 – Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: ClinVar entry from one clinical laboratory reports it as Likely Benign with no accessible supporting data. Therefore, this criterion is applied at Supporting strength.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "BP7 – 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.