rs20582

chr19-50401785-G-Achr19-50401785-G-Cchr19-50401785-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002691.4(POLD1):c.324G>A(p.Ala108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0918 in 1,611,890 control chromosomes in the GnomAD database, including 9,638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A108A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (2213 hom., cov: 32)
  • Exomes 𝑓: 0.087 (7425 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.89

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-50401785-G-A is Benign according to our data. Variant chr19-50401785-G-A is described in ClinVar as [Benign]. Clinvar id is 380219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50401785-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.324G>A	p.Ala108=	synonymous_variant	4/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.324G>A	p.Ala108=	synonymous_variant	4/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21097 AN: 151992 Hom.: 2207 Cov.: 32

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.0359

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0670

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.111 AC: 27177 AN: 245174 Hom.: 2083 AF XY: 0.113 AC XY: 15043 AN XY: 133638

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.140

Gnomad SAS exome AF: 0.200

Gnomad FIN exome AF: 0.0404

Gnomad NFE exome AF: 0.0707

Gnomad OTH exome AF: 0.0999

GnomAD4 exome AF: 0.0869 AC: 126900 AN: 1459780 Hom.: 7425 Cov.: 34 AF XY: 0.0901 AC XY: 65460 AN XY: 726348

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.167

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.0413

Gnomad4 NFE exome AF: 0.0692

Gnomad4 OTH exome AF: 0.0994

GnomAD4 genome AF: 0.139 AC: 21131 AN: 152110 Hom.: 2213 Cov.: 32 AF XY: 0.138 AC XY: 10251 AN XY: 74382

Gnomad4 AFR AF: 0.291

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.0359

Gnomad4 NFE AF: 0.0671

Gnomad4 OTH AF: 0.127

Alfa AF: 0.0757 Hom.: 656

Bravo AF: 0.153

EpiCase AF: 0.0748

EpiControl AF: 0.0763

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 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	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 16, 2016	- -

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	- -

Mandibular hypoplasia-deafness-progeroid syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 17, 2016

Variant summary: The POLD1 c.324G>A (p.Ala108Ala) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing, however, these predictions have yet to be functionally assessed. This variant was observed in the large, broad control population, ExAC, with an allele frequency of 13554/117858 (1121 homozygotes, 1/8, frequency: 0.1150028), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic POLD1 variant of 1/70422 (0.0000142), suggesting this variant is likely a benign polymorphism. Therefore, the variant of interest is classified as Benign. -

Hereditary cancer-predisposing syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.18
Dann	Benign	0.86
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.2

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

Other links and lift over

dbSNP: rs20582; hg19: chr19-50905042; COSMIC: COSV70955193; COSMIC: COSV70955193;