rs1555791103

Positions:

• chr19-50406236-G-A
• chr19-50406236-G-C
• chr19-50406236-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000440232.7(POLD1):​c.1297G>A​(p.Asp433Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. D433A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLD1 ENST00000440232.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.23

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33276504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.1297G>A	p.Asp433Asn	missense_variant	11/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.1297G>A	p.Asp433Asn	missense_variant	11/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

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

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2021

This sequence change replaces aspartic acid with asparagine at codon 433 of the POLD1 protein (p.Asp433Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. 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). 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2023

The p.D433N variant (also known as c.1297G>A), located in coding exon 10 of the POLD1 gene, results from a G to A substitution at nucleotide position 1297. The aspartic acid at codon 433 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. 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	Benign	0.13
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;.;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;.;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.6	D;.;.;.
REVEL	Benign	0.11
Sift	Benign	0.064	T;.;.;.
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.040	B;.;.;B
Vest4		0.33
MutPred		0.51		Gain of MoRF binding (P = 0.0356);Gain of MoRF binding (P = 0.0356);Gain of MoRF binding (P = 0.0356);Gain of MoRF binding (P = 0.0356);
MVP		0.55
MPC		1.3
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.33
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1555791103; hg19: chr19-50909493; COSMIC: COSV105939220; COSMIC: COSV105939220;