Variant rs775264944 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002691.4(POLD1):c.2972G>A(p.Cys991Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000017 in 1,412,698 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000017 ( 1 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.22

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 Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.2972G>A	p.Cys991Tyr	missense_variant	24/27	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.2972G>A	p.Cys991Tyr	missense_variant	24/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000527

AC:

AN:

170720

Hom.:

AF XY:

0.0000750

AC XY:

AN XY:

93386

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000215

GnomAD4 exome

AF:

0.0000170

AC:

AN:

1412698

Hom.:

Cov.:

AF XY:

0.0000243

AC XY:

AN XY:

699404

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:

0.000285

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000424

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 13, 2023

Variant summary: POLD1 c.2972G>A (p.Cys991Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 170720 control chromosomes in the gnomAD database, including 1 homozygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2972G>A in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 13, 2018

- -

Colorectal cancer, susceptibility to, 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 29, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 991 of the POLD1 protein (p.Cys991Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 619714). 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. 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2024

The p.C991Y variant (also known as c.2972G>A), located in coding exon 23 of the POLD1 gene, results from a G to A substitution at nucleotide position 2972. The cysteine at codon 991 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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

Uncertain

0.34

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Benign

0.79

DEOGEN2

Benign

0.32

T;.;.;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.82

LIST_S2

Pathogenic

0.98

.;.;D;D

M_CAP

Benign

0.079

MetaRNN

Uncertain

0.51

D;D;D;D

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.7

L;.;.;L

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-1.7

N;.;.;.

REVEL

Uncertain

0.30

Sift

Benign

0.070

T;.;.;.

Sift4G

Benign

0.26

T;T;T;T

Polyphen

0.0070

B;.;.;B

Vest4

0.77

MutPred

0.50

Loss of methylation at K992 (P = 0.0204);.;.;Loss of methylation at K992 (P = 0.0204);

MVP

0.56

MPC

1.7

ClinPred

0.14

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.42

gMVP

0.59

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