rs1085308042
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000314.8(PTEN):c.131G>A(p.Gly44Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G44S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000314.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.131G>A | p.Gly44Asp | missense_variant | 2/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.650G>A | p.Gly217Asp | missense_variant | 3/10 | ||
PTEN | NM_001304718.2 | c.-575G>A | 5_prime_UTR_variant | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.131G>A | p.Gly44Asp | missense_variant | 2/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
PTEN hamartoma tumor syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Herman Laboratory, Nationwide Children's Hospital | Mar 01, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2019 | - - |
Cowden syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 08, 2023 | Variant summary: PTEN c.131G>A (p.Gly44Asp) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain (IPR003595) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251050 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.131G>A has been reported in the literature in individuals affected with Cowden Syndrome and macrocephaly (e.g., Varga_2009, Tatton-Brown_2017, Gabriel_2022), including at least once as a de novo occurrence (e.g., Tatton-Brown_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant resulted in an approximately 88% reduction in PIP3 phosphatase activity relative to wild type in an in vivo functional assay in yeast (e.g., Rodriguez-Escudero_2011). The following publications have been ascertained in the context of this evaluation (PMID: 34958143, 21828076, 28475857, 19265751). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at