Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000314.8 | MANE Select | 8515 nt | 846–2057 |
| NM_000314.7 | RefSeq Select | 8514 nt | 845–2056 |
| NM_000314.5 | Alternative | 8719 nt | 1032–2243 |
| NM_000314.4 | Alternative | 5572 nt | 1032–2243 |
| NM_000314.3 | Alternative | 3416 nt | 1032–2243 |
| NM_000314.6 | Alternative | 8718 nt | 1032–2243 |
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) | 0.69 | 4 bp |
| Donor Loss (DL) | 0.0 | 242 bp |
| Acceptor Gain (AG) | 0.38 | -14 bp |
| Donor Gain (DG) | 0.0 | 10 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Null Variant (nonsense, frameshift, canonical ±1,2 splice sites) in a gene where loss of function is a known mechanism of disease". The evidence for this variant shows: c.254-3del is at the −3 position, not in the canonical ±1 or ±2 splice site. Therefore, this criterion is not applied because the variant does not meet the canonical splice site requirement.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change or different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant." The evidence for this variant shows: no amino acid change is defined and no known pathogenic variant at this position. Therefore, this criterion is not applied due to lack of matching amino acid change or known pathogenic splicing variant.
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 de novo testing or family history data available. Therefore, this criterion is not applied due to absence of de novo evidence.
PS3 (Not Applied)
According to PTEN Pre-processing, the finding for PS3 is: "The PTEN 254-3del variant has not been functionally characterized." The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied at any strength because functional impact has not been experimentally assessed.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Prevalence of the variant in affected individuals is significantly increased compared with controls or proband specificity scores." The evidence for this variant shows: no case counts or specificity scores reported. Therefore, this criterion is not applied due to lack of case data.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain (residues 90-94, 123-130, 166-168)." The evidence for this variant shows: c.254-3del is intronic and outside defined domains. Therefore, this criterion is not applied because it is not in a hot spot or functional domain.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent in population databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population." The evidence for this variant shows: MAF = 0% in gnomAD and other controls. Therefore, this criterion is applied at Supporting strength because the variant is absent from large population datasets.
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: inheritance mode and trans observations are unknown. Therefore, this criterion is not applied due to lack of trans configuration data.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region impacting at least one residue in a catalytic motif." The evidence for this variant shows: it is an intronic deletion with no predicted protein length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "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: variant is intronic, not missense. 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." The evidence for this variant shows: no de novo assumption data available. Therefore, this criterion is not applied due to lack of de novo information.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members (≥3-4 meioses)." 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 low rate of benign missense variation and where missense is common mechanism." The evidence for this variant shows: it is intronic, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting Multiple lines of computational evidence support a deleterious effect: Splicing variants require concordance of SpliceAI and VarSeak." The evidence for this variant shows: only SpliceAI predicts a moderate impact; VarSeak data are not available. Therefore, this criterion is not applied because concordant computational evidence is incomplete.
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 recently reports variant as pathogenic." The evidence for this variant shows: not reported in ClinVar or similar. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Filtering allele frequency >0.00056 in gnomAD." The evidence for this variant shows: MAF = 0% in gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Allele frequency from 0.000043 up to 0.00056 in gnomAD." The evidence for this variant shows: MAF = 0% in gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Observed in the homozygous state in a healthy PTEN-unaffected individual." The evidence for this variant shows: no homozygous observations reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein or splicing." The evidence for this variant shows: no functional assays available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation in affected members of two or more families." The evidence for this variant shows: no segregation data. 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 LOF causes disease." The evidence for this variant shows: intronic change. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Observed in trans with a pathogenic PTEN variant." The evidence for this variant shows: no such observations. 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." The evidence for this variant shows: intronic deletion, not in a repetitive region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact." The evidence for this variant shows: SpliceAI predicts moderate impact. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP 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 alternate molecular findings reported. 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." The evidence for this variant shows: no such reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "A synonymous or intronic variant at or beyond +7/−21 with no predicted splicing impact." The evidence for this variant shows: position −3 is within the splice region and SpliceAI predicts impact. Therefore, this criterion is not applied.