chr19-50402238-C-A

Position:

• chr19-50402238-C-A

Variant summary

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

The NM_002691.4(POLD1):​c.623C>A​(p.Pro208Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.30

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.623C>A	p.Pro208Gln	missense_variant	6/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.623C>A	p.Pro208Gln	missense_variant	6/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1440250 Hom.: 0 Cov.: 34 AF XY: 0.00000280 AC XY: 2 AN XY: 714114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000468

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jun 29, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 1003133). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 208 of the POLD1 protein (p.Pro208Gln). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2024

The p.P208Q variant (also known as c.623C>A), located in coding exon 5 of the POLD1 gene, results from a C to A substitution at nucleotide position 623. The proline at codon 208 is replaced by glutamine, 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	Benign	0.095
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T;.;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.87	.;.;D;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.50	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.;.;M
MutationTaster	Benign	0.97	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.2	D;.;.;.
REVEL	Benign	0.11
Sift	Benign	0.074	T;.;.;.
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.15	B;.;.;B
Vest4		0.51
MutPred		0.54		Gain of MoRF binding (P = 0.0523);Gain of MoRF binding (P = 0.0523);Gain of MoRF binding (P = 0.0523);Gain of MoRF binding (P = 0.0523);
MVP		0.64
MPC		0.57
ClinPred		0.92	D
GERP RS		4.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.15
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs774030917; hg19: chr19-50905495;