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
OpenThe c.548delA pathogenic mutation, located in coding exon 6 of the PTEN gene, results from a deletion of one nucleotide at nucleotide position 548, causing a translational frameshift with a predicted alternate stop codon (p.K183Rfs*16). This mutation (designated as c.546delA) was reported in an individual with macrocephaly and developmental delay/autism spectrum disorder (Yeung KS et al. Mol. Autism 2017 Dec;8:66). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
"This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN K183Rfs*16 variant is a truncating mutation that results in the loss of PTEN phosphatase function, impairing its ability to negatively regulate the PI3K/AKT pathway. Functional studies have shown that such truncating mutations are oncogenic, leading to increased genome fragility and an inability to associate with chromosomal centromeres.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.03 | -52 bp |
| Donor Loss (DL) | 0.02 | 89 bp |
| Acceptor Gain (AG) | 0.0 | 76 bp |
| Donor Gain (DG) | 0.0 | -52 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines the rule for PVS1 is: 'Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific'. The evidence for this variant shows: c.548del (K183Rfs*16) is a truncating variant in PTEN resulting in loss of function and not located in the last exon. Therefore, this criterion is applied at Very Strong strength because it is a null variant in a gene where loss of function is a known mechanism of disease.
PS1 (Not Applied)
According to VCEP guidelines the rule for PS1 is: 'Strong Strength: 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. Modification Type: Disease-specific'. The evidence for this variant shows: c.548del leads to a frameshift rather than a matching amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines the rule for PS2 is: 'Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history. Modification Type: Strength'. The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines the rule for PS3 is: 'Strong Strength: 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. Modification Type: Disease-specific'. According to PTEN Pre-processing finding the evidence for PS3 is: 'The PTEN K183Rfs*16 variant is a truncating mutation that results in the loss of PTEN phosphatase function, impairing its ability to negatively regulate the PI3K/AKT pathway. Functional studies have shown that such truncating mutations are oncogenic, leading to increased genome fragility and an inability to associate with chromosomal centromeres.'. Therefore, this criterion is applied at Strong strength because functional studies demonstrate a damaging effect on PTEN activity.
PS4 (Not Applied)
According to VCEP guidelines the rule for PS4 is: 'Strong Strength: Probands with specificity score 4-15.5 (see text) OR The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. Modification Type: Strength'. The evidence for this variant shows: no case prevalence or specificity score data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines the rule for PM1 is: 'Moderate Strength: Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_000305.3). Modification Type: Disease-specific'. The evidence for this variant shows: it affects residue 183, outside the defined critical regions. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines the rule for PM2 is: 'Supporting Strength: Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%). Modification Type: Disease-specific'. The evidence for this variant shows: it is absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because it is not observed in population databases.
PM3 (Not Applied)
According to standard ACMG guidelines the rule for PM3 is: 'Moderate Strength: Detected in trans with a pathogenic variant for recessive disorders.'. The evidence for this variant shows: PTEN-associated disease is autosomal dominant and no trans observations with another pathogenic PTEN variant are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines the rule for PM4 is: 'Moderate Strength: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif, and variants causing protein extension. Modification Type: Disease-specific'. The evidence for this variant shows: it causes a frameshift leading to premature truncation rather than an in-frame indel. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines the rule for PM5 is: 'Moderate Strength: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant. Modification Type: Disease-specific'. The evidence for this variant shows: it is a frameshift, not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines the rule for PM6 is: 'Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history. Modification Type: Strength'. The evidence for this variant shows: no de novo assumption data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines the rule for PP1 is: 'Supporting Strength: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. Modification Type: Disease-specific'. The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines the rule for PP2 is: 'Supporting Strength: Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.'. The evidence for this variant shows: it is a frameshift variant, not a missense variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines the rule for PP3 is: 'Supporting Strength: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak. Missense variants: REVEL score > 0.7. Modification Type: Disease-specific'. The evidence for this variant shows: SpliceAI max score is 0.03, and no computational deleterious predictions are present. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines the rule for PP4 is: 'Supporting Strength: Phenotype is highly specific for a disease with a single genetic etiology.'. The evidence for this variant shows: no phenotype or family history data are provided. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines the rule for PP5 is: 'Supporting Strength: Reputable source reports variant as pathogenic but evidence not available.'. The evidence for this variant shows: ClinVar lists this variant as Pathogenic from one clinical laboratory. Therefore, this criterion is applied at Supporting strength because a reputable database classifies it as pathogenic.
BA1 (Not Applied)
According to VCEP guidelines the rule for BA1 is: 'Stand Alone Strength: gnomAD Filtering allele frequency >0.00056 (0.056%).'. The evidence for this variant shows: it is absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines the rule for BS1 is: 'Strong Strength: gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%). Modification Type: Disease-specific'. The evidence for this variant shows: it is absent from population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines the rule for BS2 is: 'Strong Strength: Observed in the homozygous state in a healthy or PHTS-unaffected individual. One observation if homozygous status confirmed, two if not confirmed. Modification Type: Disease-specific'. The evidence for this variant shows: no homozygous observations in healthy individuals are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines the rule for BS3 is: 'Strong Strength: Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.'. The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines the rule for BS4 is: 'Strong Strength: Lack of segregation in affected members of two or more families. Modification Type: Disease-specific'. The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines the rule for BP1 is: 'Supporting Strength: Missense variant in a gene where only truncating variants cause disease.'. The evidence for this variant shows: it is a truncating variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines the rule for BP2 is: 'Supporting Strength: Observed in trans with a pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic PTEN variants. Modification Type: Disease-specific'. The evidence for this variant shows: no cis or trans observations with other pathogenic variants are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines the rule for BP3 is: 'Supporting Strength: In-frame insertions or deletions in repetitive regions with no known function.'. The evidence for this variant shows: it is a frameshift variant. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines the rule for BP4 is: 'Supporting Strength: Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak. Missense variants: REVEL scores < 0.5. Modification Type: Disease-specific'. The evidence for this variant shows: in silico predictions do not support lack of impact for a truncating variant. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines the rule for BP5 is: 'Supporting Strength: Variant found in a case with an alternate molecular basis for disease.'. The evidence for this variant shows: no alternate molecular basis has been reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines the rule for BP6 is: 'Supporting Strength: Reputable source reports variant as benign.'. The evidence for this variant shows: no such benign reports are available. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines the rule for BP7 is: 'Supporting Strength: A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice.'. The evidence for this variant shows: it is a frameshift variant. Therefore, this criterion is not applied.