19-50402476-G-C

Position:

• chr19-50402476-G-C

Variant summary

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

The NM_002691.4(POLD1):​c.781G>C​(p.Val261Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79

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.781G>C	p.Val261Leu	missense_variant	7/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.781G>C	p.Val261Leu	missense_variant	7/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.781G>C (p.V261L) alteration is located in exon 7 (coding exon 6) of the POLD1 gene. This alteration results from a G to C substitution at nucleotide position 781, causing the valine (V) at amino acid position 261 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.;T
Eigen	Benign	0.077
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.11	T;.;.;.
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.067	B;.;.;B
Vest4		0.64
MutPred		0.60		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP		0.49
MPC		0.46
ClinPred		0.85	D
GERP RS		4.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.40
gMVP		0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50905733;