rs1064792943
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_002691.4(POLD1):c.2612_2623del(p.Leu871_Asn874del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000657 in 152,204 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D870D) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Consequence
POLD1
NM_002691.4 inframe_deletion
NM_002691.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.69
Genes affected
POLD1 (HGNC:9175): (DNA polymerase delta 1, catalytic subunit) This gene encodes the 125-kDa catalytic subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_002691.4.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.2612_2623del | p.Leu871_Asn874del | inframe_deletion | 21/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.2612_2623del | p.Leu871_Asn874del | inframe_deletion | 21/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2022 | In-frame deletion of 4 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2020 | In summary, this variant is a novel in-frame deletion with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Experimental studies have not been published for this variant and the functional importance of the deleted amino acids is not known. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a POLD1-related disease. This sequence change deletes 12 nucleotides from exon 21 of the POLD1 mRNA (c.2612_2623delTGCTGTGCAACC). This leads to the deletion of 4 amino acid residue(s) in the POLD1 protein (p.Leu871_Asn874del) but otherwise preserves the integrity of the reading frame. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 25, 2020 | The c.2612_2623del12 variant (also known as p.L871_N874del) is located in coding exon 20 of the POLD1 gene. This variant results from an in-frame deletion of 12 nucleotides at positions 2612 to 2623. This results in the in-frame deletion of 4 amino acid residues at codons 871 to 874. This amino acid region is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at