19-50398888-G-C

Position:

• chr19-50398888-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002691.4(POLD1):​c.37G>C​(p.Val13Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V13M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07805106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.37G>C	p.Val13Leu	missense_variant	2/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.37G>C	p.Val13Leu	missense_variant	2/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 11, 2020

This sequence change replaces valine with leucine at codon 13 of the POLD1 protein (p.Val13Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. 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: "Tolerated"; PolyPhen-2: "Not Available"; 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.71
DEOGEN2	Benign	0.19	T;.;.;.;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.70	.;.;T;T;T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.078	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.20	N;.;.;.;N;.
MutationTaster	Benign	0.93	N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.39	N;.;.;.;.;.
REVEL	Benign	0.029
Sift	Benign	0.68	T;.;.;.;.;.
Sift4G	Benign	0.69	T;T;D;T;T;D
Polyphen		0.0	B;.;.;.;B;.
Vest4		0.14
MutPred		0.19		Gain of glycosylation at P11 (P = 0.0862);Gain of glycosylation at P11 (P = 0.0862);Gain of glycosylation at P11 (P = 0.0862);Gain of glycosylation at P11 (P = 0.0862);Gain of glycosylation at P11 (P = 0.0862);Gain of glycosylation at P11 (P = 0.0862);
MVP		0.21
MPC		0.18
ClinPred		0.072	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.028
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-50902145;