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"This variant has been reported in ClinVar as Uncertain significance (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) | 0.34 | 14 bp |
| Donor Loss (DL) | 0.07 | 61 bp |
| Acceptor Gain (AG) | 0.85 | 1 bp |
| Donor Gain (DG) | 0.0 | 417 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines: 'Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific'. The evidence for this variant shows an intronic alteration at c.210-14, outside the canonical splice donor/acceptor sites (±1/±2). Therefore, PVS1 is not applied because PTEN PVS1 requires disruption of the canonical splice sites for null effect.
PS1 (Not Applied)
According to VCEP guidelines: 'PS1 Strong: 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 or established analogous pathogenic variant. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to VCEP guidelines: 'PS2 Strong: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.' There is no de novo or parental testing information available for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines: 'PS3 Strong: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. RNA, mini-gene, or other assay shows impact on splicing.' PTEN pre-processing did not identify this variant in functional assay datasets. Therefore, PS3 is not applied due to lack of functional study data.
PS4 (Not Applied)
According to VCEP guidelines: PS4 relates to increased prevalence in affected individuals or proband specificity scores. There are no case or cohort data for this variant. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines: 'PM1 Moderate: Located in a mutational hot spot and/or critical and well-established functional domain (residues 90-94, 123-130, 166-168).' This variant is intronic and not within a defined PTEN functional domain. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines: 'PM2 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. Therefore, PM2 is applied at Supporting strength because the variant is absent from population databases as specified.
PM3 (Not Applied)
According to VCEP guidelines: PM3 addresses recessive inheritance with in trans observations. There is no evidence of this variant observed in trans with a pathogenic PTEN variant. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to VCEP guidelines: 'PM4 Moderate: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.' This variant does not alter protein length. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines: 'PM5 Moderate: Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.' This variant is intronic and not a missense change. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to VCEP guidelines: PM6 addresses presumed de novo observations without confirmation. There is no de novo information for this variant. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines: PP1 addresses co-segregation in multiple affected family members. No segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG: 'PP2 Supporting: Missense variant in a gene that has a low rate of benign missense variation where missense is a common mechanism.' This variant is intronic. Therefore, PP2 is not applied.
PP3 (Supporting)
According to VCEP guidelines: 'PP3 Supporting: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak.' The evidence for this variant shows SpliceAI maximum score of 0.85 predicting acceptor gain. Therefore, PP3 is applied at Supporting strength due to predicted splicing alteration.
PP4 (Not Applied)
According to standard ACMG: 'PP4 Supporting: Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.' No phenotype data were provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG: 'PP5 Supporting: Reputable source recently reports variant as pathogenic without available evidence.' The only ClinVar entry is Uncertain significance. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines: 'BA1 Stand Alone: gnomAD Filtering allele frequency >0.00056 (0.056%).' The variant frequency is 0%. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines: 'BS1 Strong: gnomAD Filtering allele frequency from 0.000043 up to 0.00056.' The variant frequency is 0%. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines: 'BS2 Strong: Observed in homozygous state in healthy individual.' No homozygous observations are reported. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines: 'BS3 Strong: Functional studies show no damaging effect on protein function.' No functional studies demonstrating lack of impact are available. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines: 'BS4 Strong: Lack of segregation in affected members of two or more families.' No segregation data exist. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG: 'BP1 Supporting: Missense variant in gene where only truncating variants cause disease.' This variant is intronic. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to VCEP guidelines: 'BP2 Supporting: Observed in trans with a pathogenic PTEN variant.' No such observations. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to VCEP guidelines: 'BP3 Supporting: In-frame indels in repetitive region.' This variant is not an in-frame indel. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines: 'BP4 Supporting: Computational evidence suggests no impact.' In silico predictions are mixed and SpliceAI predicts impact. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to VCEP guidelines: 'BP5 Supporting: Variant found in a case with an alternate molecular basis.' No alternate molecular basis is documented. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG: 'BP6 Supporting: Reputable source reports variant as benign without evidence.' No such benign report exists. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines: 'BP7 Supporting: A synonymous or intronic variant at or beyond +7/-21 with no predicted splicing impact.' Although this variant is at -14 (beyond -7), SpliceAI predicts a significant splicing impact. Therefore, BP7 is not applied.