10-87925562-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000314.8(PTEN):c.209+5G>C variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000314.8 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.209+5G>C | splice_region_variant, intron_variant | Intron 3 of 8 | ENST00000371953.8 | NP_000305.3 | ||
PTEN | NM_001304717.5 | c.728+5G>C | splice_region_variant, intron_variant | Intron 4 of 9 | NP_001291646.4 | |||
PTEN | NM_001304718.2 | c.-541-5484G>C | intron_variant | Intron 2 of 8 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and both in silico predictors and evolutionary conservation support a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18626099, 11146448) -
PTEN hamartoma tumor syndrome Uncertain:1
This variant has not been reported in the literature in individuals with PTEN-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 3 of the PTEN gene. It does not directly change the encoded amino acid sequence of the PTEN protein, but it affects a nucleotide within the consensus splice site of the intron. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the c.209+5G nucleotide in the PTEN gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10232405, 23695273, 20712882,16014636, 28677221). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at