chr19-50415779-G-C

Position:

• chr19-50415779-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002691.4(POLD1):​c.2773G>C​(p.Val925Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000706 in 1,415,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V925M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.01

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.2773G>C	p.Val925Leu	missense_variant	22/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.2773G>C	p.Val925Leu	missense_variant	22/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1415778 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 700656

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: 9.17e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Nov 20, 2023

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 925 of the POLD1 protein (p.Val925Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1047788). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLD1 protein function. 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	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;.;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	3.0	M;.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.9	D;.;.;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.95	P;.;.;P
Vest4		0.73
MutPred		0.66		Gain of sheet (P = 0.1945);.;.;Gain of sheet (P = 0.1945);
MVP		0.66
MPC		1.4
ClinPred		0.99	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.77

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: rs746950229; hg19: chr19-50919036;