10-87931094-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_000314.8(PTEN):c.253+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 Likely pathogenic (★).
Frequency
Consequence
NM_000314.8 splice_region, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.253+5G>C | splice_region_variant, intron_variant | Intron 4 of 8 | ENST00000371953.8 | NP_000305.3 | ||
PTEN | NM_001304717.5 | c.772+5G>C | splice_region_variant, intron_variant | Intron 5 of 9 | NP_001291646.4 | |||
PTEN | NM_001304718.2 | c.-498+5G>C | splice_region_variant, intron_variant | Intron 3 of 8 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
PTEN hamartoma tumor syndrome Pathogenic:1
Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 4 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.253+5G nucleotide in the PTEN gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 24375884, 28677221; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 968699). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 4 of the PTEN gene. It does not directly change the encoded amino acid sequence of the PTEN protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at