Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| 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 |
| NM_000314.8 | MANE Select | 8515 nt | 846–2057 |
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) | 0.01 | 10 bp |
| Donor Loss (DL) | 0.0 | -124 bp |
| Acceptor Gain (AG) | 0.0 | 117 bp |
| Donor Gain (DG) | 0.0 | 189 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the PVS1 rule for PTEN is determined by the PTEN PVS1 decision tree. The variant NM_000314.8:c.1027-10C>A lies outside the canonical ±1/±2 splice sites and there is no evidence of loss‐of‐function by splicing. Therefore, PVS1 is not applied because the variant is intronic beyond the critical splice positions with no predicted impact.
PS1 (Not Applied)
According to VCEP guidelines, PS1 requires the same amino acid change as a known pathogenic variant or an equivalent splicing impact. This variant is intronic with no coding or splicing match to a known pathogenic PTEN variant. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to VCEP guidelines, PS2 requires confirmed de novo occurrence. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to PTEN pre-processing, no functional studies (in vitro or in vivo) have been reported for NM_000314.8:c.1027-10C>A and the variant was not found in the PTEN functional assay file. Therefore, PS3 is not applied due to lack of functional evidence.
PS4 (Not Applied)
According to VCEP guidelines, PS4 requires increased prevalence in affected individuals or proband specificity scores. No case‐level or case‐control data are available for this variant. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 applies to variants in critical PTEN functional domains (residues 90-94, 123-130, 166-168). This intronic variant does not lie within a defined hotspot or functional domain. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, PM2 Supporting is 'Absent in population Databases present at <0.00001 allele frequency in gnomAD'. The variant is not found in gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength because the variant is absent from large population databases.
PM3 (Not Applied)
According to VCEP guidelines, PM3 applies to recessive disorders observed in trans with a pathogenic variant. PTEN-associated conditions are dominant and no trans observations are available. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to VCEP guidelines, PM4 applies to protein length changes (in-frame indels or stop-loss). This variant is intronic without protein length alteration. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines, PM5 requires a novel missense change at a residue with a known pathogenic missense. This is intronic. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to VCEP guidelines, PM6 applies to presumed de novo cases. No de novo information is available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 requires co-segregation data. No segregation data are reported. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies to missense in genes with low benign missense rate. This is intronic. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 Supporting requires concordant computational evidence for deleterious effect (REVEL>0.7 or splicing algorithms). In silico predictors are mixed and SpliceAI=0.01 predicts no impact. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 requires highly specific phenotype data. No phenotype data are available. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 requires a reputable source reporting pathogenicity. This variant is not in ClinVar or literature. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 Stand Alone requires gnomAD allele frequency >0.056%. The variant MAF=0%. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 Strong requires allele frequency 0.0043%–0.056%. The variant MAF=0%. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 applies to homozygous observations in healthy individuals. No such data exist. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 requires functional studies showing no damaging effect. No splicing or protein assays are available. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 requires lack of segregation. No segregation studies exist. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 applies to missense variants in LOF genes. This is intronic. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to VCEP guidelines, BP2 applies to trans observations with a pathogenic PTEN variant. No data are available. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame indels in repeat regions. This is intronic. Therefore, BP3 is not applied.
BP4 (Supporting)
According to VCEP guidelines, BP4 Supporting is 'Multiple lines of computational evidence suggest no impact on gene or gene product.' SpliceAI=0.01 and CADD=2.28 predict no impact. Therefore, BP4 is applied at Supporting strength.
BP5 (Not Applied)
According to VCEP guidelines, BP5 applies when an alternate molecular basis explains disease. No alternate diagnosis data are available. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 requires a reputable source reporting benign impact. No such source exists. Therefore, BP6 is not applied.
BP7 (Supporting)
According to VCEP guidelines, BP7 Supporting is 'A synonymous or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact.' This variant is at −10 (within the eligible region) and SpliceAI predicts no impact. Therefore, BP7 is applied at Supporting strength.