19-50407153-C-T

Position:

• chr19-50407153-C-T

Variant summary

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

The NM_002691.4(POLD1):​c.1665C>T​(p.Val555Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000979 in 1,607,936 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.54

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 19-50407153-C-T is Benign according to our data. Variant chr19-50407153-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 239248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407153-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BS2: High AC in GnomAd4 at 87 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.1665C>T	p.Val555Val	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.1665C>T	p.Val555Val	synonymous_variant	13/27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152162 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000783 AC: 194 AN: 247632 Hom.: 2 AF XY: 0.000858 AC XY: 115 AN XY: 134024

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.000517

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.00102 AC: 1487 AN: 1455658 Hom.: 4 Cov.: 34 AF XY: 0.00107 AC XY: 776 AN XY: 723070

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.000512

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.000999

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152278 Hom.: 0 Cov.: 31 AF XY: 0.000497 AC XY: 37 AN XY: 74456

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000992 Hom.: 0

Bravo AF: 0.000536

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000890

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 30, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2017	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	Genetic Services Laboratory, University of Chicago	Jan 07, 2021	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	POLD1: BP4, BP7, BS1 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 26, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 06, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 18, 2015	This alteration is classified as likely 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. -

Colorectal cancer, susceptibility to, 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLD1 p.Val555= variant was not identified in the literature. The variant was identified in dbSNP (rs150238541) as “with likely benign allele” and ClinVar (classified as likely benign by Ambry Genetics, GeneDx, True Health Diagnostics and 2 other submitters; and as benign by Invitae and Prevention Genetics). The variant was identified in control databases in 206 of 279,020 chromosomes (2 homozygous) at a frequency of 0.0007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 43 of 30,490 chromosomes (freq: 0.001), European in 142 of 126,522 chromosomes (freq: 0.001), Other in 4 of 7138 chromosomes (freq: 0.0006), Finnish in 13 of 24,740 chromosomes (freq: 0.0005), Ashkenazi Jewish in 1 of 10,192 chromosomes (freq: 0.0001), African in 2 of 24,900 chromosomes (freq: 0.00008), and Latino in 1 of 35,130 chromosomes (freq: 0.00003), while it was not observed in the East Asian population. The p.Val555= 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. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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	-0.45
CADD	Benign	6.6
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs150238541; hg19: chr19-50910410;