19-50413515-T-C

Variant names:

• chr19-50413515-T-C
• rs1274607
• NM_002691.4:c.2244T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002691.4(POLD1):​c.2244T>C​(p.Ser748Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,607,560 control chromosomes in the GnomAD database, including 4,681 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (2474 hom., cov: 33)
  • Exomes 𝑓: 0.013 (2207 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.99
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• POLD1-related polyposis and colorectal cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal cancer, susceptibility to, 10

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• mandibular hypoplasia-deafness-progeroid syndrome

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
• Polymerase proofreading-related adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency 120

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• non-severe combined immunodeficiency due to polymerase delta deficiency

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-50413515-T-C is Benign according to our data. Variant chr19-50413515-T-C is described in ClinVar as Benign. ClinVar VariationId is 380228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.2244T>C	p.Ser748Ser	synonymous_variant	Exon 18 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.2244T>C	p.Ser748Ser	synonymous_variant	Exon 18 of 27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes AF: 0.0994 AC: 15117 AN: 152018 Hom.: 2458 Cov.: 33

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0452

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0458

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.0790

GnomAD2 exomes AF: 0.0315 AC: 7538 AN: 239014 AF XY: 0.0255

Gnomad AFR exome AF: 0.342

Gnomad AMR exome AF: 0.0200

Gnomad ASJ exome AF: 0.0202

Gnomad EAS exome AF: 0.000984

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0131 AC: 19027 AN: 1455424 Hom.: 2207 Cov.: 30 AF XY: 0.0126 AC XY: 9102 AN XY: 723730

African (AFR) AF: 0.342 AC: 11338 AN: 33188

American (AMR) AF: 0.0225 AC: 984 AN: 43764

Ashkenazi Jewish (ASJ) AF: 0.0214 AC: 559 AN: 26068

East Asian (EAS) AF: 0.000713 AC: 28 AN: 39264

South Asian (SAS) AF: 0.0372 AC: 3184 AN: 85594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52772

Middle Eastern (MID) AF: 0.0219 AC: 126 AN: 5760

European-Non Finnish (NFE) AF: 0.000993 AC: 1101 AN: 1108866

Other (OTH) AF: 0.0284 AC: 1707 AN: 60148

GnomAD4 genome AF: 0.0998 AC: 15183 AN: 152136 Hom.: 2474 Cov.: 33 AF XY: 0.0971 AC XY: 7227 AN XY: 74396

African (AFR) AF: 0.334 AC: 13857 AN: 41474

American (AMR) AF: 0.0450 AC: 688 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 91 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5170

South Asian (SAS) AF: 0.0461 AC: 222 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00196 AC: 133 AN: 67982

Other (OTH) AF: 0.0829 AC: 175 AN: 2110

Alfa AF: 0.0416 Hom.: 2457

Bravo AF: 0.113

Asia WGS AF: 0.0700 AC: 245 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Nov 06, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 22, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

May 19, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The POLD1 c.2244T>C (p.Ser748Ser) 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. This variant was found in 4143/92154 control chromosomes (542 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.3593498 (3117/8674). This frequency is about 25298 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Colorectal cancer, susceptibility to, 10 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

May 20, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 20, 2025

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The synonymous variant NM_001308632.1(POLD1):c.2322T>C (p.Ser774=) has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 380228 as of 2025-01-02). The p.Ser774= variant is observed in 593/5,008 (11.8411%) alleles from individuals of 1kG All background in 1kG, indicating it is a common benign variant. The p.Ser774= variant is not predicted to disrupt the existing donor splice site 7bp upstream by any splice site algorithm. The p.Ser774= variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Benign. -

Carcinoma of colon Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLD1 p.Ser748= variant was identified in dbSNP (ID: rs1274607) as “With Benign allele”, ClinVar (classified benign by GeneDx, Invitae and Ambry Genetics), and in control databases in 10176 of 264892 chromosomes (1384 homozygous) at a frequency of 0.04 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 7802 (1337 homozygous) of 22948 chromosomes (freq: 0.34), Other in 124 (3 homozygous) of 6258 chromosomes (freq: 0.02), Latino in 670 (13 homozygous) of 33116 chromosomes (freq: 0.02), European Non-Finnish in 216 of 120574 chromosomes (freq: 0.002), Ashkenazi Jewish in 195 (2 homozygous) of 9974 chromosomes (freq: 0.02), East Asian in 21 of 17784 chromosomes (freq: 0.001), and South Asian in 1148 (29 homozygous) of 29792 chromosomes (freq: 0.04), while not observed in the European Finnish population. The p.Ser748Ser 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	-0.87
CADD	Benign	0.23
DANN	Benign	0.45
PhyloP100		-2.0
PromoterAI		0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1274607; hg19: chr19-50916772;