19-50401933-C-T
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_002691.4(POLD1):c.463+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 1,613,970 control chromosomes in the GnomAD database, including 286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_002691.4 intron
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.463+9C>T | intron_variant | Intron 4 of 26 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0237 AC: 3605AN: 152138Hom.: 148 Cov.: 32
GnomAD3 exomes AF: 0.00629 AC: 1580AN: 251030Hom.: 60 AF XY: 0.00452 AC XY: 613AN XY: 135714
GnomAD4 exome AF: 0.00232 AC: 3388AN: 1461714Hom.: 137 Cov.: 34 AF XY: 0.00199 AC XY: 1446AN XY: 727170
GnomAD4 genome AF: 0.0237 AC: 3615AN: 152256Hom.: 149 Cov.: 32 AF XY: 0.0231 AC XY: 1718AN XY: 74434
ClinVar
Submissions by phenotype
not specified Benign:6
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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:3
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Variant summary: The POLD1 c.463+9C>T variant involves the alteration of a non-conserved intronic nucleotide with 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 901/121202 control chromosomes (39 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0801541 (832/10380). This frequency is about 5643 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, considering the high allele frequency of this variant in the African population, this variant is classified as benign. -
Polymerase proofreading-related adenomatous polyposis;C3896578:Familial colorectal cancer type X Benign:1
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Colorectal cancer, susceptibility to, 10 Benign:1
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Hereditary cancer-predisposing syndrome Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at