Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_006231.4 | MANE Select | 7823 nt | 28–6888 |
| NM_006231.2 | Alternative | 7859 nt | 45–6905 |
| NM_006231.3 | RefSeq Select | 8024 nt | 210–7070 |
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) | 0.0 | 384 bp |
| Donor Loss (DL) | 0.0 | 331 bp |
| Acceptor Gain (AG) | 0.03 | -32 bp |
| Donor Gain (DG) | 0.0 | -255 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 (N151I), not a null variant. Therefore, this criterion is not applied at Very Strong strength because the variant type does not meet the null variant definition.
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 previously established pathogenic variant resulting in N151I. Therefore, this criterion is not applied at Strong strength because there is no matching known pathogenic 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 information on de novo occurrence or parental testing. Therefore, this criterion is not applied at Strong strength due to lack of de novo data.
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 has been performed. Therefore, this criterion is not applied at Strong strength because functional data are unavailable.
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 or prevalence data in affected individuals. Therefore, this criterion is not applied at Strong strength due to lack of prevalence data.
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". The evidence for this variant shows: no information indicating mutation hotspot or critical domain at residue 151. Therefore, this criterion is not applied at Moderate strength.
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: MAF=0% and the variant is not present in gnomAD or other population databases. 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: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no data on trans configuration with a pathogenic variant. Therefore, this criterion is not applied at Moderate strength.
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, not an in-frame indel or stop-loss. Therefore, this criterion is not applied at Moderate strength.
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". The evidence for this variant shows: no other pathogenic missense change reported at residue N151. Therefore, this criterion is not 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 assumption or parental data. Therefore, this criterion is not applied at Moderate strength.
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 family segregation data. Therefore, this criterion is not applied at Supporting strength.
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 the overall missense constraint of POLE. Therefore, this criterion is not applied at Supporting strength.
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 (e.g., conservation, splicing impact)". The evidence for this variant shows: computational tools (CADD, PolyPhen, MetaSVM, MetaLR, PrimateAI, REVEL=0.15, SpliceAI=0.03) predict benign impact. Therefore, this criterion is not applied at Supporting strength because predictions do not support deleterious effect.
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". The evidence for this variant shows: no phenotypic information provided. Therefore, this criterion is not applied at Supporting strength.
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: not found in ClinVar or other sources. Therefore, this criterion is not applied at Supporting strength.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied at Stand Alone strength because allele frequency is not high.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied at Strong strength.
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 adult cohorts. Therefore, this criterion is not applied at Strong strength.
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 at Strong strength.
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. Therefore, this criterion is not applied at Strong strength.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: unclear whether only LoF is disease mechanism for POLE. Therefore, this criterion is not applied at Supporting strength.
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 data on cis/trans with other variants. Therefore, this criterion is not applied at Supporting strength.
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: variant is missense, not in-frame indel. Therefore, this criterion is not applied at Supporting strength.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: CADD, PolyPhen, MetaSVM, MetaLR, PrimateAI, REVEL=0.15 predict benign impact and SpliceAI=0.03 predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because computational evidence uniformly suggests no functional impact.
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 case data with alternate molecular findings. Therefore, this criterion is not applied at Supporting strength.
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: not found in such sources. Therefore, this criterion is not 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 at Supporting strength.