19-50402067-G-C

Position:

chr19-50402067-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002691.4(POLD1):c.532G>C(p.Gly178Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,034 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 1 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 3.05

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:

POLD1 (HGNC:):

POLD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09199464).

BS2

High AC in GnomAdExome4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.532G>C	p.Gly178Arg	missense_variant	5/27	ENST00000440232.7	NP_002682.2	P28340A0A024R4F4Q59FA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7 linkuse as main transcript	c.532G>C	p.Gly178Arg	missense_variant	5/27	1	NM_002691.4	ENSP00000406046.1		P28340

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD3 exomes

AF:

0.0000798

AC:

AN:

250686

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461744

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

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

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29056344, 35780178, 37105989, 32265515, 34326862) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 23, 2019	- -

POLD1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 26, 2023

The POLD1 c.532G>C variant is predicted to result in the amino acid substitution p.Gly178Arg. This variant has been reported in three related individuals, two of which had bladder cancer (Wang et al. 2021. PubMed ID: 32265515). This variant has also been reported in tumor specimens (Table S2, Campbell et al. 2017. PubMed ID: 29056344). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50905324-G-C) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/420703/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Colorectal cancer, susceptibility to, 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 178 of the POLD1 protein (p.Gly178Arg). This variant is present in population databases (rs140707092, gnomAD 0.02%). 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: 420703). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome;C5935622:Immunodeficiency 120

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 11, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.21

T;.;.;.;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.50

LIST_S2

Uncertain

0.86

.;.;D;D;D

M_CAP

Benign

0.039

MetaRNN

Benign

0.092

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.46

N;.;.;.;N

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.4

N;.;.;.;.

REVEL

Benign

0.058

Sift

Benign

0.28

T;.;.;.;.

Sift4G

Benign

0.25

T;T;D;T;T

Polyphen

0.11

B;.;.;.;B

Vest4

0.32

MutPred

0.59

Gain of MoRF binding (P = 0.0187);Gain of MoRF binding (P = 0.0187);Gain of MoRF binding (P = 0.0187);Gain of MoRF binding (P = 0.0187);Gain of MoRF binding (P = 0.0187);

MVP

0.43

MPC

0.73

ClinPred

0.043

GERP RS

3.3

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.074

gMVP

0.50

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