rs747165215
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_006231.4(POLE):c.5378+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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_006231.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250606Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135520
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461078Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726922
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 14, 2023 | 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. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products involving part of intron retention (Invitae). ClinVar contains an entry for this variant (Variation ID: 560846). Disruption of this splice site has been observed in individual(s) with ovarian cancer (PMID: 32885271). This variant is present in population databases (rs747165215, gnomAD 0.003%). This sequence change affects a donor splice site in intron 39 of the POLE gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in POLE are known to be pathogenic (PMID: 23230001, 25948378, 30503519). - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 13, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at