19-50403499-T-C

Position:

• chr19-50403499-T-C

Variant summary

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

The NM_002691.4(POLD1):​c.1144T>C​(p.Ser382Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.55

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	UniProt
POLD1	NM_002691.4	c.1144T>C	p.Ser382Pro	missense_variant	10/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.1144T>C	p.Ser382Pro	missense_variant	10/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460856 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726814

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Invitae

Aug 06, 2017

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. This variant has not been reported in the literature in individuals with POLD1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with proline at codon 382 of the POLD1 protein (p.Ser382Pro). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and proline. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2023

The p.S382P variant (also known as c.1144T>C), located in coding exon 9 of the POLD1 gene, results from a T to C substitution at nucleotide position 1144. The serine at codon 382 is replaced by proline, an amino acid with 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	Pathogenic	0.92
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Uncertain	0.58	D;.;.;D
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.80
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	.;.;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;.;M
MutationTaster	Benign	0.87	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.6	D;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.12	T;.;.;.
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.0020	B;.;.;B
Vest4		0.56
MutPred		0.65		Loss of disorder (P = 0.2121);Loss of disorder (P = 0.2121);Loss of disorder (P = 0.2121);Loss of disorder (P = 0.2121);
MVP		0.48
MPC		0.80
ClinPred		0.43	T
GERP RS		-2.4
Varity_R		0.95
gMVP		0.94

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: rs1555790556; hg19: chr19-50906756; COSMIC: COSV70954114; COSMIC: COSV70954114;