19-50401932-G-T

Variant names:

• chr19-50401932-G-T
• rs1726802
• NM_002691.4:c.463+8G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002691.4(POLD1):​c.463+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0918 in 1,613,850 control chromosomes in the GnomAD database, including 9,681 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2241 hom., cov: 32)
  • Exomes 𝑓: 0.087 (7440 hom.)
• Consequence: POLD1 NM_002691.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002784
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.41
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-50401932-G-T is Benign according to our data. Variant chr19-50401932-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 371890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.463+8G>T		splice_region_variant, intron_variant	Intron 4 of 26	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.463+8G>T		splice_region_variant, intron_variant	Intron 4 of 26	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21193 AN: 152004 Hom.: 2235 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.0359

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0670

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.110 AC: 27712 AN: 250892 AF XY: 0.112

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.0407

Gnomad NFE exome AF: 0.0701

Gnomad OTH exome AF: 0.0992

GnomAD4 exome AF: 0.0869 AC: 126987 AN: 1461728 Hom.: 7440 Cov.: 35 AF XY: 0.0901 AC XY: 65483 AN XY: 727174

African (AFR) AF: 0.298 AC: 9964 AN: 33470

American (AMR) AF: 0.105 AC: 4715 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2764 AN: 26120

East Asian (EAS) AF: 0.165 AC: 6561 AN: 39698

South Asian (SAS) AF: 0.197 AC: 16991 AN: 86250

European-Finnish (FIN) AF: 0.0414 AC: 2212 AN: 53400

Middle Eastern (MID) AF: 0.145 AC: 838 AN: 5766

European-Non Finnish (NFE) AF: 0.0692 AC: 76934 AN: 1111924

Other (OTH) AF: 0.0995 AC: 6008 AN: 60382

GnomAD4 genome AF: 0.140 AC: 21224 AN: 152122 Hom.: 2241 Cov.: 32 AF XY: 0.138 AC XY: 10290 AN XY: 74380

African (AFR) AF: 0.293 AC: 12168 AN: 41490

American (AMR) AF: 0.103 AC: 1575 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 367 AN: 3470

East Asian (EAS) AF: 0.152 AC: 780 AN: 5146

South Asian (SAS) AF: 0.200 AC: 966 AN: 4826

European-Finnish (FIN) AF: 0.0359 AC: 381 AN: 10610

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0670 AC: 4555 AN: 67978

Other (OTH) AF: 0.126 AC: 266 AN: 2110

Alfa AF: 0.0991 Hom.: 489

Bravo AF: 0.151

Asia WGS AF: 0.185 AC: 642 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -

Nov 02, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

Colorectal cancer, susceptibility to, 10 Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2016

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 18, 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.463+8G>T variant involves the alteration of a non-conserved intronic nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing, although these predictions have yet to be functionally assessed. This variant was observed in the large, broad control population, ExAC, with an allele frequency of 13864/121128 (1142 homozygotes, 1/8, frequency: 0.1144574), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic POLD1 variant of 1/70422 (0.0000142), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

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. -

Dec 23, 2024

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The splice region variant NM_001308632.1(POLD1):c.463+8G>T has been reported to ClinVar as Benign/Likely benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 371890 as of 2024-12-05). The c.463+8G>T variant is not predicted to disrupt the existing donor splice site 6bp upstream by any splice site algorithm. The c.463+8G>T 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. -

Mandibular hypoplasia-deafness-progeroid syndrome Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.28
DANN	Benign	0.83
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs1726802; hg19: chr19-50905189; COSMIC: COSV70955584; COSMIC: COSV70955584;