rs879254134
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The ENST00000440232.7(POLD1):āc.3103G>Cā(p.Glu1035Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000835 in 1,556,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1035D) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000440232.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.3103G>C | p.Glu1035Gln | missense_variant | 25/27 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.3103G>C | p.Glu1035Gln | missense_variant | 25/27 | 1 | NM_002691.4 | ENSP00000406046 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152150Hom.: 0 Cov.: 34
GnomAD4 exome AF: 0.00000427 AC: 6AN: 1403892Hom.: 0 Cov.: 33 AF XY: 0.00000433 AC XY: 3AN XY: 693080
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152266Hom.: 0 Cov.: 34 AF XY: 0.0000537 AC XY: 4AN XY: 74434
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 24, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 02, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19296856, 32041611) - |
POLD1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 12, 2023 | The POLD1 c.3103G>C variant is predicted to result in the amino acid substitution p.Glu1035Gln. This variant was reported in an individual with lipodystrophy (Table S4, Dron. 2020. PubMed ID: 32041611). This variant is reported in 0.0056% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50920337-G-C), and is reported as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/246168/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1035 of the POLD1 protein (p.Glu1035Gln). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 246168). 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 not expected to disrupt POLD1 protein function with a negative predictive value of 80%. 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