chr19-50414972-G-A
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_002691.4(POLD1):c.2546G>A(p.Arg849His) variant causes a missense change. The variant allele was found at a frequency of 0.00734 in 1,590,186 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R849C) has been classified as Uncertain significance.
Frequency
Consequence
NM_002691.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.2546G>A | p.Arg849His | missense_variant | 20/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.2546G>A | p.Arg849His | missense_variant | 20/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00666 AC: 1014AN: 152190Hom.: 10 Cov.: 33
GnomAD3 exomes AF: 0.00783 AC: 1714AN: 218902Hom.: 13 AF XY: 0.00796 AC XY: 949AN XY: 119290
GnomAD4 exome AF: 0.00742 AC: 10666AN: 1437878Hom.: 65 Cov.: 32 AF XY: 0.00736 AC XY: 5256AN XY: 713736
GnomAD4 genome AF: 0.00664 AC: 1012AN: 152308Hom.: 10 Cov.: 33 AF XY: 0.00650 AC XY: 484AN XY: 74476
ClinVar
Submissions by phenotype
not specified Benign:5
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 22, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 07, 2016 | - - |
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 25, 2016 | Variant summary: The c.2546G>A (p.Arg849His) in POLD1 gene is a missense change that involves a mildly conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at an overall frequency 0.01 (728/69008 chrs tested) including 4 homozygotes. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000142). The variant is cited as Benign/Polymorphism by a reputable database/clinical laboratory and published report. Taking together, the variant was classified as Benign. - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 11, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | POLD1: BS1, BS2 - |
Colorectal cancer, susceptibility to, 10 Benign:3
Benign, criteria provided, single submitter | clinical testing | Counsyl | Jun 09, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | May 11, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 20, 2015 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Jan 12, 2018 | - - |
Carcinoma of colon Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The POLD1 p.Arg849His variant was identified in 2 of 58 proband chromosomes (frequency: 0.03) from individuals or families with colorectal cancer (Talseth-Palmer 2016). The variant was also identified in dbSNP (ID: rs3218775 as With Likely benign allele), ClinVar (classified as benign by Invitae, Counsyl, GeneDx, Ambry Genetics, and two other clinical laboratories), and LOVD 3.0 (classified as benign and likely benign). The variant was not identified in Cosmic, or MutDB. The variant was identified in control databases in 1854 of 245284 chromosomes (13 homozygous) at a frequency of 0.008, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). This variant was seen in the following populations: African in 27 of 21986 chromosomes (freq: 0.001), Other in 63 of 5744 chromosomes (freq: 0.01), Latino in 209 of 30752 chromosomes (freq: 0.01), European Non-Finnish in 954 of 110672 chromosomes (freq: 0.01), Ashkenazi Jewish in 383 of 9020 chromosomes (freq: 0.04), European Finnish in 174 of 22218 chromosomes (freq: 0.01), and South Asian in 44 of 28122 chromosomes (freq: 0.002); it was not observed in the East Asian population. The p.Arg849 residue is conserved in mammals but not in more distantly related organisms. However, 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although the available information suggests a benign role. This variant is classified as likely benign. - |
Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 11, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at