19-50406301-C-T
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2
The NM_002691.4(POLD1):c.1362C>T(p.Arg454=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R454R) has been classified as Likely benign.
Frequency
Consequence
NM_002691.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.1362C>T | p.Arg454= | synonymous_variant | 11/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.1362C>T | p.Arg454= | synonymous_variant | 11/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152082Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251188Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135814
GnomAD4 exome AF: 0.0000540 AC: 79AN: 1461730Hom.: 0 Cov.: 36 AF XY: 0.0000523 AC XY: 38AN XY: 727170
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152082Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74274
ClinVar
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 18, 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. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 25, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | POLD1: BP4, BP7 - |
Colorectal cancer, susceptibility to, 10 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 14, 2015 | This alteration is classified as likely 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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 23, 2021 | - - |
Polymerase proofreading-related adenomatous polyposis Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The POLD1 p.Arg454= variant was not identified in the literature. The variant was identified in dbSNP (rs773075581) as “with likely benign allele” and ClinVar (classified as likely benign by GeneDx, Invitae and Ambry Genetics). The variant was identified in control databases in 16 of 251,188 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 14 of 113,624 chromosomes (freq: 0.0001), African in 1 of 16,246 chromosomes (freq: 0.00006), and South Asian in 1 of 30,610 chromosomes (freq: 0.00003); it was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish or Other populations. The p.Arg454= variant is not expected to have clinical significance because it does not result in a change of amino acid and occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence. However, 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at