rs45605236

Positions:

• chr19-50409206-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The ENST00000440232.7(POLD1):​c.1977C>T​(p.Ile659=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,612,682 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (20 hom.)
• Consequence: POLD1 ENST00000440232.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 2.16

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BP6: Variant 19-50409206-C-T is Benign according to our data. Variant chr19-50409206-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 221165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50409206-C-T is described in Lovd as [Benign]. Variant chr19-50409206-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.16 with no splicing effect.
• BS2: High AC in GnomAd4 at 431 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.1977C>T	p.Ile659=	synonymous_variant	16/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.1977C>T	p.Ile659=	synonymous_variant	16/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152240 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00706

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00251 AC: 629 AN: 250800 Hom.: 1 AF XY: 0.00251 AC XY: 340 AN XY: 135628

Gnomad AFR exome AF: 0.000865

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000556

Gnomad NFE exome AF: 0.00386

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00365 AC: 5337 AN: 1460324 Hom.: 20 Cov.: 31 AF XY: 0.00355 AC XY: 2579 AN XY: 726580

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.00400

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000583

Gnomad4 NFE exome AF: 0.00436

Gnomad4 OTH exome AF: 0.00348

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152358 Hom.: 3 Cov.: 32 AF XY: 0.00287 AC XY: 214 AN XY: 74518

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00705

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.00395

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00362 Hom.: 1

Bravo AF: 0.00307

EpiCase AF: 0.00387

EpiControl AF: 0.00433

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2016	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. -
Likely 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 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 25, 2021	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	POLD1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 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.1977C>T (p.Ile659Ile) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 288/119080 control chromosomes (1 homozygote) at a frequency of 0.0024185, which is approximately 170 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory in ClinVar has classified this variant as benign. The variant of interest has not been reported in affected individuals via publications, to our knowledge. Taken together, this variant is classified as Benign. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 21, 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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 01, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -

Colorectal cancer, susceptibility to, 10 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Polymerase proofreading-related adenomatous polyposis Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLD1 p.Ile659= variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs45605236) “With other allele”, ClinVar (classified benign by Invitae, GeneDx, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano, and likely benign by Genetic Services Laboratory (University of Chicago)), Clinvitae (3x), and in control databases in 683 (1 homozygous) of 276786 chromosomes at a frequency of 0.002 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 25 of 23988 chromosomes (freq: 0.001), Other in 13 of 6462 chromosomes (freq: 0.002), Latino in 127 (1 homozygous) of 34414 chromosomes (freq: 0.004), European Non-Finnish in 481 of 126400 chromosomes (freq: 0.004), Ashkenazi Jewish in 24 of 10134 chromosomes (freq: 0.002), European Finnish in 12 of 25748 chromosomes (freq: 0.0005), and South Asian in 1 of 30776 chromosomes (freq: 0.00003) while not observed in the East Asian population. The p.Ile659= 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	9.9
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs45605236; hg19: chr19-50912463; COSMIC: COSV101486739; COSMIC: COSV101486739;