rs2230244

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002691.4(POLD1):c.1173C>T(p.Asp391=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00481 in 1,614,038 control chromosomes in the GnomAD database, including 324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 160 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 164 hom. )

Consequence

POLD1
NM_002691.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -2.23

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 19-50403528-C-T is Benign according to our data. Variant chr19-50403528-C-T is described in ClinVar as [Benign]. Clinvar id is 380706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403528-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.23 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.1173C>T	p.Asp391=	synonymous_variant	10/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7 linkuse as main transcript	c.1173C>T	p.Asp391=	synonymous_variant	10/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0253

AC:

3857

AN:

152200

Hom.:

159

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0867

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0135

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.00698

AC:

1756

AN:

251472

Hom.:

AF XY:

0.00501

AC XY:

681

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0904

Gnomad AMR exome

AF:

0.00642

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00267

AC:

3896

AN:

1461720

Hom.:

164

Cov.:

AF XY:

0.00228

AC XY:

1658

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0896

Gnomad4 AMR exome

AF:

0.00686

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000161

Gnomad4 OTH exome

AF:

0.00626

GnomAD4 genome

AF:

0.0254

AC:

3873

AN:

152318

Hom.:

160

Cov.:

AF XY:

0.0247

AC XY:

1839

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0868

Gnomad4 AMR

AF:

0.0135

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0168

Hom.:

Bravo

AF:

0.0295

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2015	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	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 06, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 14, 2020	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2016	Variant summary: The POLD1 c.1173C>T (p.Asp391Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation Taster predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 999/121398 control chromosomes (42 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0874495 (910/10406). This frequency is about 6156 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is a common benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as Benign. -

Colorectal cancer, susceptibility to, 10

Benign:2

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

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 25, 2017	- -
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. -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The POLD1 p.Asp391= variant was identified in dbSNP (ID: rs2230244) â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, ClinVar (classified benign by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), and in control databases in 2422 (97 homozygous) of 277198 chromosomes at a frequency of 0.009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2125 (97 homozygous) of 24026 chromosomes (freq: 0.09), Other in 25 of 6466 chromosomes (freq: 0.004), Latino in 230 of 34420 chromosomes (freq: 0.007), European Non-Finnish in 39 of 126692 chromosomes (freq: 0.0003), Ashkenazi Jewish in 1 of 10152 chromosomes (freq: 0.0001), European Finnish in 1 of 25792 chromosomes (freq: 0.00004), and South Asian in 1 of 30780 chromosomes (freq: 0.00003), while not observed in the East Asian population. The p.Asp391= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

Cadd

Benign

0.44

Dann

Benign

0.53

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