rs3218767
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1
The NM_002691.4(POLD1):c.2154+13_2154+14insA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 1,588,032 control chromosomes in the GnomAD database, including 176 homozygotes. 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 -16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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POLD1 | NM_002691.4 | c.2154+13_2154+14insA | intron_variant | Intron 17 of 26 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0190 AC: 2900AN: 152234Hom.: 93 Cov.: 32
GnomAD3 exomes AF: 0.00519 AC: 1214AN: 234120Hom.: 40 AF XY: 0.00372 AC XY: 474AN XY: 127308
GnomAD4 exome AF: 0.00185 AC: 2662AN: 1435680Hom.: 82 Cov.: 32 AF XY: 0.00159 AC XY: 1127AN XY: 710336
GnomAD4 genome AF: 0.0191 AC: 2906AN: 152352Hom.: 94 Cov.: 32 AF XY: 0.0183 AC XY: 1365AN XY: 74494
ClinVar
Submissions by phenotype
not provided Benign:3
Variant summary: The POLD1 c.2154+13_2154+14insA variant involves the insertion of an intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 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 686/112178 control chromosomes (26 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0667447 (627/9394). This frequency is about 4699 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, this variant is classified as benign. -
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not specified Benign:2
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Carcinoma of colon Benign:1
The POLD1 c.2154+13_2154+14insA variant was not identified in the literature nor was it identified in MutDB. The variant was identified in dbSNP (ID: rs3218767 as With Benign allele) and ClinVar (2x as benign). The variant was identified in control databases in 1751 of 261160 chromosomes (64 homozygous) at a frequency of 0.007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1563 of 23566 chromosomes (freq: 0.07), Latino in 153 of 32366 chromosomes (freq: 0.005), Other in 13 of 6046 chromosomes (freq: 0.002), European Non-Finnish in 20 of 118628 chromosomes (freq: 0.0002), Ashkenazi Jewish in 1 of 8814 chromosomes (freq: 0.0001), South Asian in 1 of 28168 chromosomes (freq: 0.00004), while the variant was not observed in the East Asian or Finnish populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
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