19-50414972-G-A

Position:

chr19-50414972-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002691.4(POLD1):c.2546G>A(p.Arg849His) variant causes a missense change. The variant allele was found at a frequency of 0.00734 in 1,590,186 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R849C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0066 ( 10 hom., cov: 33)

Exomes 𝑓: 0.0074 ( 65 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 3.81

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074485242).

BP6

Variant 19-50414972-G-A is Benign according to our data. Variant chr19-50414972-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 220865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50414972-G-A is described in Lovd as [Benign]. Variant chr19-50414972-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00742 (10666/1437878) while in subpopulation MID AF= 0.0189 (108/5706). AF 95% confidence interval is 0.016. There are 65 homozygotes in gnomad4_exome. There are 5256 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1012 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.2546G>A	p.Arg849His	missense_variant	20/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7 linkuse as main transcript	c.2546G>A	p.Arg849His	missense_variant	20/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00666

AC:

1014

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.0187

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.0446

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00555

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00772

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.00783

AC:

1714

AN:

218902

Hom.:

AF XY:

0.00796

AC XY:

949

AN XY:

119290

show subpopulations

Gnomad AFR exome

AF:

0.00120

Gnomad AMR exome

AF:

0.00688

Gnomad ASJ exome

AF:

0.0419

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00150

Gnomad FIN exome

AF:

0.00778

Gnomad NFE exome

AF:

0.00890

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.00742

AC:

10666

AN:

1437878

Hom.:

Cov.:

AF XY:

0.00736

AC XY:

5256

AN XY:

713736

show subpopulations

Gnomad4 AFR exome

AF:

0.00119

Gnomad4 AMR exome

AF:

0.00770

Gnomad4 ASJ exome

AF:

0.0436

Gnomad4 EAS exome

AF:

0.0000519

Gnomad4 SAS exome

AF:

0.00177

Gnomad4 FIN exome

AF:

0.00735

Gnomad4 NFE exome

AF:

0.00732

Gnomad4 OTH exome

AF:

0.00877

GnomAD4 genome

AF:

0.00664

AC:

1012

AN:

152308

Hom.:

Cov.:

AF XY:

0.00650

AC XY:

484

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.0446

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00555

Gnomad4 NFE

AF:

0.00769

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.00899

Hom.:

Bravo

AF:

0.00685

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00977

AC:

ExAC

AF:

0.00672

AC:

814

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 07, 2016	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 25, 2016	Variant summary: The c.2546G>A (p.Arg849His) in POLD1 gene is a missense change that involves a mildly conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at an overall frequency 0.01 (728/69008 chrs tested) including 4 homozygotes. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000142). The variant is cited as Benign/Polymorphism by a reputable database/clinical laboratory and published report. Taking together, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	POLD1: BS1, BS2 -

Colorectal cancer, susceptibility to, 10

Benign:3

Benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 20, 2015	This alteration is classified as 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. -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 12, 2018	- -

Carcinoma of colon

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The POLD1 p.Arg849His variant was identified in 2 of 58 proband chromosomes (frequency: 0.03) from individuals or families with colorectal cancer (Talseth-Palmer 2016). The variant was also identified in dbSNP (ID: rs3218775 as With Likely benign allele), ClinVar (classified as benign by Invitae, Counsyl, GeneDx, Ambry Genetics, and two other clinical laboratories), and LOVD 3.0 (classified as benign and likely benign). The variant was not identified in Cosmic, or MutDB. The variant was identified in control databases in 1854 of 245284 chromosomes (13 homozygous) at a frequency of 0.008, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). This variant was seen in the following populations: African in 27 of 21986 chromosomes (freq: 0.001), Other in 63 of 5744 chromosomes (freq: 0.01), Latino in 209 of 30752 chromosomes (freq: 0.01), European Non-Finnish in 954 of 110672 chromosomes (freq: 0.01), Ashkenazi Jewish in 383 of 9020 chromosomes (freq: 0.04), European Finnish in 174 of 22218 chromosomes (freq: 0.01), and South Asian in 44 of 28122 chromosomes (freq: 0.002); it was not observed in the East Asian population. The p.Arg849 residue is conserved in mammals but not in more distantly related organisms. However, 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although the available information suggests a benign role. This variant is classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

T;.;.;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.25

LIST_S2

Uncertain

0.97

.;.;D;D

MetaRNN

Benign

0.0074

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.92

L;.;.;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.5

N;.;.;.

REVEL

Benign

0.052

Sift

Benign

0.36

T;.;.;.

Sift4G

Benign

0.41

T;T;T;T

Polyphen

0.025

B;.;.;B

Vest4

0.17

MVP

0.48

MPC

0.78

ClinPred

0.0068

GERP RS

3.5

Varity_R

0.061

gMVP

0.38

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