rs2230245

Positions:

• chr19-50406508-C-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.1485C>T​(p.Thr495Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,580,166 control chromosomes in the GnomAD database, including 11,895 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (966 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10929 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -5.27

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-50406508-C-T is Benign according to our data. Variant chr19-50406508-C-T is described in ClinVar as [Benign]. Clinvar id is 258787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50406508-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.1485C>T	p.Thr495Thr	synonymous_variant	12/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.1485C>T	p.Thr495Thr	synonymous_variant	12/27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes AF: 0.0987 AC: 15005 AN: 152050 Hom.: 964 Cov.: 32

Gnomad AFR AF: 0.0411

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.0853

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.00847

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.117

GnomAD3 exomes AF: 0.105 AC: 20740 AN: 198334 Hom.: 1366 AF XY: 0.109 AC XY: 11565 AN XY: 106122

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.0585

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.0122

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.119 AC: 169994 AN: 1427996 Hom.: 10929 Cov.: 35 AF XY: 0.120 AC XY: 84765 AN XY: 707616

Gnomad4 AFR exome AF: 0.0393

Gnomad4 AMR exome AF: 0.0620

Gnomad4 ASJ exome AF: 0.173

Gnomad4 EAS exome AF: 0.00795

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.0987 AC: 15013 AN: 152170 Hom.: 966 Cov.: 32 AF XY: 0.100 AC XY: 7449 AN XY: 74374

Gnomad4 AFR AF: 0.0411

Gnomad4 AMR AF: 0.0852

Gnomad4 ASJ AF: 0.173

Gnomad4 EAS AF: 0.00829

Gnomad4 SAS AF: 0.137

Gnomad4 FIN AF: 0.170

Gnomad4 NFE AF: 0.124

Gnomad4 OTH AF: 0.118

Alfa AF: 0.112 Hom.: 690

Bravo AF: 0.0890

Asia WGS AF: 0.0770 AC: 265 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 25, 2016	Variant summary: The c.1485C>T (p.Thr495=) in POLD1 gene is a synonymous change that involves a non-conserved nucleotide. 2/5 programs in Alamut predict that this variant may affect the normal splicing pattern by weakening the neighboring donor site, however no functional studies supporting these predictions were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.124 (5844/47134 chrs tested), including numerous homozygous occurrences. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000142). The variant of interest has not, to our knowledge, been reported in publications or cited by multiple reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Colorectal cancer, susceptibility to, 10 Benign:2

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

Mandibular hypoplasia-deafness-progeroid syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

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	-0.52
CADD	Benign	2.9
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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: rs2230245; hg19: chr19-50909765;