19-50401785-G-T

Variant names:

• chr19-50401785-G-T
• rs20582
• NM_002691.4:c.324G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002691.4(POLD1):​c.324G>T​(p.Ala108Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,612,072 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A108A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0090 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (28 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -3.89
• Publications: 20 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=-0.83).
• BP6: Variant 19-50401785-G-T is Benign according to our data. Variant chr19-50401785-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00896 (1363/152158) while in subpopulation AFR AF = 0.0302 (1252/41486). AF 95% confidence interval is 0.0288. There are 21 homozygotes in GnomAd4. There are 644 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002691.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	NM_002691.4	MANE Select	c.324G>T	p.Ala108Ala	synonymous	Exon 4 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.324G>T	p.Ala108Ala	synonymous	Exon 3 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.324G>T	p.Ala108Ala	synonymous	Exon 4 of 27	NP_001243778.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.324G>T	p.Ala108Ala	synonymous	Exon 4 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.324G>T	p.Ala108Ala	synonymous	Exon 4 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.324G>T	p.Ala108Ala	synonymous	Exon 4 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1356 AN: 152040 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00248 AC: 608 AN: 245174 AF XY: 0.00220

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00310

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00121 AC: 1769 AN: 1459914 Hom.: 28 Cov.: 34 AF XY: 0.00115 AC XY: 838 AN XY: 726412

African (AFR) AF: 0.0350 AC: 1171 AN: 33472

American (AMR) AF: 0.00237 AC: 106 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00303 AC: 79 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51780

Middle Eastern (MID) AF: 0.00747 AC: 43 AN: 5758

European-Non Finnish (NFE) AF: 0.000160 AC: 178 AN: 1111794

Other (OTH) AF: 0.00293 AC: 177 AN: 60346

GnomAD4 genome AF: 0.00896 AC: 1363 AN: 152158 Hom.: 21 Cov.: 32 AF XY: 0.00865 AC XY: 644 AN XY: 74416

African (AFR) AF: 0.0302 AC: 1252 AN: 41486

American (AMR) AF: 0.00386 AC: 59 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67972

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.0000996 Hom.: 1571

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 24, 2017

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 03, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 28, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Sep 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 26, 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.324G>T (p.Ala108Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 358/117858 control chromosomes (6 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0311842 (296/9492). This frequency is about 2195 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. In addition, one clinical diagnostic laboratory in ClinVar ahs 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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Hereditary cancer-predisposing syndrome Benign:3

May 15, 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.324G>T (p.Ala108=) has been reported to ClinVar as Benign/Likely benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 220913 as of 2025-05-01).The p.Ala108= variant is not predicted to disrupt the existing acceptor splice site 8bp upstream by any splice site algorithm. The p.Ala108= 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.

Oct 04, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 22, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: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

Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome Benign:1

May 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome;C5935622:Immunodeficiency 120 Benign:1

Oct 18, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.036
DANN	Benign	0.84
PhyloP100		-3.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.2
Mutation Taster		=100/0	polymorphism

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: rs20582; hg19: chr19-50905042;