chr19-50401916-C-T

Position:

chr19-50401916-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002691.4(POLD1):c.455C>T(p.Ala152Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000595 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: 1.71

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04330492).

BP6

Variant 19-50401916-C-T is Benign according to our data. Variant chr19-50401916-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 239348.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=1, Uncertain_significance=3}. Variant chr19-50401916-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.455C>T	p.Ala152Val	missense_variant	4/27	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.455C>T	p.Ala152Val	missense_variant	4/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000474

AC:

119

AN:

251100

Hom.:

AF XY:

0.000435

AC XY:

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000811

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000594

AC:

869

AN:

1461774

Hom.:

Cov.:

AF XY:

0.000609

AC XY:

443

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000716

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000598

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00106

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000770

Hom.:

Bravo

AF:

0.000495

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000511

AC:

EpiCase

AF:

0.00120

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2024	Variant summary: POLD1 c.455C>T (p.Ala152Val) 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 0.00047 in 251100 control chromosomes. The observed variant frequency is approximately 33.36 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05). c.455C>T has been reported in the literature in individuals with a personal or family history of hereditary cancer (e.g. Guindalini_2022, Bhai_2021, de Oliveira_2022, Erdem_2020, Mur_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 32283892, 35264596, 32792570, 37990341, 35534704). ClinVar contains an entry for this variant (Variation ID: 239348). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 17, 2020	DNA sequence analysis of the POLD1 gene demonstrated a sequence change, c.455C>T, in exon 4 that results in an amino acid change, p.Ala152Val. This sequence change does not appear to have been previously described in patients with POLD1-related disorders and has been described in the gnomAD database with a frequency of 0.09% in the European sub-population (dbSNP rs41563714). The p.Ala152Val change affects a highly conserved amino acid residue located in a domain of the POLD1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala152Val substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala152Val change remains unknown at this time. -

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2020	This variant is associated with the following publications: (PMID: 25620207) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 18, 2019	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2024	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. -

POLD1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Colorectal cancer, susceptibility to, 10

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

T;.;.;.;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.91

.;.;D;D;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.043

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

L;.;.;.;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.8

N;.;.;.;.

REVEL

Benign

0.12

Sift

Benign

0.25

T;.;.;.;.

Sift4G

Benign

0.43

T;T;D;T;T

Polyphen

0.042

B;.;.;.;B

Vest4

0.34

MVP

0.49

MPC

0.35

ClinPred

0.014

GERP RS

4.0

Varity_R

0.16

gMVP

0.52

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