chr19-50403485-A-G
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_002691.4(POLD1):c.1138-8A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000574 in 1,605,808 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_002691.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.1138-8A>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.1138-8A>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000540 AC: 82AN: 151770Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000606 AC: 152AN: 251010Hom.: 0 AF XY: 0.000494 AC XY: 67AN XY: 135638
GnomAD4 exome AF: 0.000578 AC: 840AN: 1453922Hom.: 1 Cov.: 30 AF XY: 0.000569 AC XY: 412AN XY: 723888
GnomAD4 genome AF: 0.000540 AC: 82AN: 151886Hom.: 0 Cov.: 32 AF XY: 0.000579 AC XY: 43AN XY: 74252
ClinVar
Submissions by phenotype
not provided Benign:8
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | POLD1: BS1, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 11, 2021 | This variant is associated with the following publications: (PMID: 28577310, 28423643) - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 03, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 30, 2016 | - - |
Colorectal cancer, susceptibility to, 10 Benign:6
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 19, 2023 | This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Sep 14, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
not specified Benign:2
Likely 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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 07, 2020 | Variant summary: POLD1 c.1138-8A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 3/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00061 in 251010 control chromosomes, predominantly at a frequency of 0.0016 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 113 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as benign (2x) and likely benign (6x). Based on the evidence outlined above, the variant was classified as benign. - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 16, 2020 | - - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Jan 24, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at