Variant 19-50414933-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002691.4(POLD1):c.2507A>T(p.Asn836Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,194 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 (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.61

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.2507A>T	p.Asn836Ile	missense_variant	20/27	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.2507A>T	p.Asn836Ile	missense_variant	20/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

Jul 27, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 836 of the POLD1 protein (p.Asn836Ile). 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: 1022549). 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 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

T;.;.;T

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

0.98

.;.;D;D

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Benign

-0.29

MutationAssessor

Pathogenic

4.3

H;.;.;H

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-8.6

D;.;.;.

REVEL

Uncertain

0.43

Sift

Pathogenic

0.0

D;.;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

0.99

D;.;.;D

Vest4

0.88

MutPred

0.80

Loss of catalytic residue at N836 (P = 0.0306);.;.;Loss of catalytic residue at N836 (P = 0.0306);

MVP

0.75

MPC

1.8

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.91

gMVP

0.89

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

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