chr19-50402094-G-C

Position:

• chr19-50402094-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000440232.7(POLD1):​c.559G>C​(p.Val187Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,364 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V187M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: POLD1 ENST00000440232.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.559G>C	p.Val187Leu	missense_variant	5/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.559G>C	p.Val187Leu	missense_variant	5/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250230 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461364 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726988

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 01, 2023

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 187 of the POLD1 protein (p.Val187Leu). This variant is present in population databases (rs775620863, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1026487). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLD1 protein function. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2024

The p.V187L variant (also known as c.559G>C), located in coding exon 4 of the POLD1 gene, results from a G to C substitution at nucleotide position 559. The valine at codon 187 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated 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	Uncertain	0.50
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;.;.;T
Eigen	Benign	0.10
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	.;.;T;D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.59	D;D;D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.5	M;.;.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.6	D;.;.;.;.
REVEL	Benign	0.20
Sift	Uncertain	0.012	D;.;.;.;.
Sift4G	Uncertain	0.050	T;D;D;D;T
Polyphen		0.60	P;.;.;.;P
Vest4		0.58
MutPred		0.61		Gain of disorder (P = 0.1109);Gain of disorder (P = 0.1109);Gain of disorder (P = 0.1109);Gain of disorder (P = 0.1109);Gain of disorder (P = 0.1109);
MVP		0.58
MPC		0.69
ClinPred		0.92	D
GERP RS		4.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.42
gMVP		0.71

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

Other links and lift over

dbSNP: rs775620863; hg19: chr19-50905351;