chr19-50415496-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_002691.4(POLD1):c.2623C>T(p.Arg875Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R875H) has been classified as Uncertain significance.
Frequency
Consequence
NM_002691.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.2623C>T | p.Arg875Cys | missense_variant | 21/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.2623C>T | p.Arg875Cys | missense_variant | 21/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249610Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135536
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1460996Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726820
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74372
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 21, 2017 | - - |
Mandibular hypoplasia-deafness-progeroid syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 07, 2018 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. - |
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 08, 2023 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLD1 protein function. ClinVar contains an entry for this variant (Variation ID: 439256). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is present in population databases (rs751565067, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 875 of the POLD1 protein (p.Arg875Cys). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at