rs1022546996
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_ModeratePM2PP3_Strong
The NM_002691.4(POLD1):c.2954-2A>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,128 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).
Frequency
Consequence
NM_002691.4 splice_acceptor
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.2954-2A>C | splice_acceptor_variant | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.2954-2A>C | splice_acceptor_variant | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000617 AC: 1AN: 162082Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 88424
GnomAD4 exome Cov.: 34
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74308
ClinVar
Submissions by phenotype
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | 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. Studies have shown that disruption of this splice site results in skipping of exon 24, but is expected to preserve the integrity of the reading-frame (Invitae). ClinVar contains an entry for this variant (Variation ID: 578009). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change affects an acceptor splice site in intron 23 of the POLD1 gene. Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLD1 protein are associated with PPAP (polymerase proofreading–associated polyposis) (PMID: 23263490, 23447401). However, loss-of-function variants that result in an absent or severely disrupted POLD1 protein, and missense variants outside the exonuclease domain, are unlikely to be associated with PPAP. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at