Variant 19-50417072-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_002691.4(POLD1):c.3095G>C(p.Arg1032Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,401,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.05

Variant links:

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]

POLD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.3095G>C	p.Arg1032Pro	missense_variant	25/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7 linkuse as main transcript	c.3095G>C	p.Arg1032Pro	missense_variant	25/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1401834

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691820

show subpopulations

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:

9.26e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Colorectal cancer, susceptibility to, 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 20, 2021

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 23, 2023

The p.R1032P variant (also known as c.3095G>C), located in coding exon 24 of the POLD1 gene, results from a G to C substitution at nucleotide position 3095. The arginine at codon 1032 is replaced by proline, an amino acid with dissimilar 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

Pathogenic

0.69

BayesDel_addAF

Benign

-0.0095

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;.;.;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.96

.;.;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.53

D;D;D;D

MetaSVM

Benign

-0.31

MutationAssessor

Pathogenic

3.4

M;.;.;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.2

D;.;.;.

REVEL

Benign

0.27

Sift

Uncertain

0.0020

D;.;.;.

Sift4G

Uncertain

0.011

D;D;D;D

Polyphen

0.96

D;.;.;D

Vest4

0.45

MutPred

0.40

Gain of glycosylation at R1032 (P = 0.0131);.;.;Gain of glycosylation at R1032 (P = 0.0131);

MVP

0.80

MPC

1.7

ClinPred

0.98

GERP RS

3.0

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.92

gMVP

0.90

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over