rs777866589

Positions:

Variant summary

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

The NM_002691.4(POLD1):c.1504G>A(p.Asp502Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000425 in 1,435,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D502E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000034 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.10

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=0.035048127).

BP6

Variant 19-50406992-G-A is Benign according to our data. Variant chr19-50406992-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 414774.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4, Benign=1}.

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.1504G>A	p.Asp502Asn	missense_variant	13/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7 linkuse as main transcript	c.1504G>A	p.Asp502Asn	missense_variant	13/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000341

AC:

AN:

146796

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000339

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000212

AC:

AN:

240080

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

129920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000929

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.0000435

AC:

AN:

1288822

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

638574

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.98e-7

Gnomad4 OTH exome

AF:

0.0000407

GnomAD4 genome

AF:

0.0000341

AC:

AN:

146796

Hom.:

Cov.:

AF XY:

0.0000280

AC XY:

AN XY:

71470

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000339

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.000189

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 29, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2020	Has not been previously published as pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 7704014, 27161865, 10074927, 20951805, 24816253) -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 07, 2021	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 06, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 01, 2019

- -

Colorectal cancer, susceptibility to, 10

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.68

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;.;.;T

Eigen

Benign

-0.018

Eigen_PC

Benign

0.017

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.037

MetaRNN

Benign

0.035

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.;.;M

MutationTaster

Benign

0.97

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.1

N;.;.;.

REVEL

Benign

0.13

Sift

Benign

0.22

T;.;.;.

Sift4G

Benign

0.16

T;T;T;T

Polyphen

0.081

B;.;.;B

Vest4

0.16

MutPred

0.33

Gain of MoRF binding (P = 0.0474);Gain of MoRF binding (P = 0.0474);Gain of MoRF binding (P = 0.0474);Gain of MoRF binding (P = 0.0474);

MVP

0.58

MPC

0.84

ClinPred

0.084

GERP RS

3.5

Varity_R

0.15

gMVP

0.23

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