19-50402723-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002691.4(POLD1):​c.952G>C​(p.Glu318Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

POLD1
NM_002691.4 missense

Scores

8
10
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.17
Variant links:
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLD1NM_002691.4 linkc.952G>C p.Glu318Gln missense_variant Exon 8 of 27 ENST00000440232.7 NP_002682.2 P28340A0A024R4F4Q59FA0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLD1ENST00000440232.7 linkc.952G>C p.Glu318Gln missense_variant Exon 8 of 27 1 NM_002691.4 ENSP00000406046.1 P28340

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1
Mar 03, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid with glutamine at codon 318 of the POLD1 protein (p.Glu318Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POLD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1
Nov 18, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.E318Q variant (also known as c.952G>C), located in coding exon 7 of the POLD1 gene, results from a G to C substitution at nucleotide position 952. The glutamic acid at codon 318 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T;.;.;T
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
.;.;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Uncertain
-0.023
T
MutationAssessor
Pathogenic
3.6
H;.;.;H
PrimateAI
Uncertain
0.79
T
PROVEAN
Uncertain
-2.8
D;.;.;.
REVEL
Uncertain
0.57
Sift
Uncertain
0.0010
D;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
1.0
D;.;.;D
Vest4
0.88
MutPred
0.89
Loss of ubiquitination at K323 (P = 0.1486);Loss of ubiquitination at K323 (P = 0.1486);Loss of ubiquitination at K323 (P = 0.1486);Loss of ubiquitination at K323 (P = 0.1486);
MVP
0.83
MPC
0.74
ClinPred
0.98
D
GERP RS
3.8
Varity_R
0.93
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs775232133; hg19: chr19-50905980; API