rs2230247

Positions:

• chr19-50407036-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002691.4(POLD1):​c.1548C>T​(p.Ala516Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,613,600 control chromosomes in the GnomAD database, including 853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (432 hom., cov: 30)
  • Exomes 𝑓: 0.0045 (421 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.0150

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 19-50407036-C-T is Benign according to our data. Variant chr19-50407036-C-T is described in ClinVar as [Benign]. Clinvar id is 380637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407036-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.015 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.1548C>T	p.Ala516Ala	synonymous_variant	13/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.1548C>T	p.Ala516Ala	synonymous_variant	13/27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6317 AN: 152108 Hom.: 428 Cov.: 30

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0113 AC: 2822 AN: 250414 Hom.: 181 AF XY: 0.00832 AC XY: 1127 AN XY: 135390

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.00934

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000646

Gnomad OTH exome AF: 0.00671

GnomAD4 exome AF: 0.00447 AC: 6536 AN: 1461374 Hom.: 421 Cov.: 34 AF XY: 0.00392 AC XY: 2853 AN XY: 727028

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.00310

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000265

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.0417 AC: 6341 AN: 152226 Hom.: 432 Cov.: 30 AF XY: 0.0403 AC XY: 2996 AN XY: 74422

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.0216 Hom.: 81

Bravo AF: 0.0480

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 10, 2020	- -
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, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 06, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 19, 2016	Variant summary: The POLD1 c.1548C>T (p.Ala516Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not affect any ESE site. This variant was found in 1638/120504 control chromosomes (117 homozygotes) at a frequency of 0.0135929, which is approximately 957 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as benign. -

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	- -

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.Ala516= variant was identified in dbSNP (ID: rs2230247) “With Benign allele”, ClinVar (classified benign by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), and in control databases in 3896 (256 homozygous) of 276142 chromosomes at a frequency of 0.01 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 3408 (250 homozygous) of 23952 chromosomes (freq: 0.14), Other in 42 of 6448 chromosomes (freq: 0.007), Latino in 328 (5 homozygous) of 34418 chromosomes (freq: 0.01), European Non-Finnish in 77 (1 homozygous) of 125860 chromosomes (freq: 0.0006), Ashkenazi Jewish in 32 of 10134 chromosomes (freq: 0.003), and South Asian in 9 of 30778 chromosomes (freq: 0.0003), while not observed in the East Asian and European Finnish populations. The p.Ala516= 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	-0.44
CADD	Benign	9.8
DANN	Benign	0.56

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: rs2230247; hg19: chr19-50910293;