19-50417153-C-T

Variant names:

• chr19-50417153-C-T
• rs3212330
• NM_002691.4:c.3121-19C>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.3121-19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,580,788 control chromosomes in the GnomAD database, including 3,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.088 (1883 hom., cov: 34)
  • Exomes 𝑓: 0.014 (1703 hom.)
• Consequence: POLD1 NM_002691.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.329
• Publications: 4 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

ENSG00000142539 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-50417153-C-T is Benign according to our data. Variant chr19-50417153-C-T is described in ClinVar as Benign. ClinVar VariationId is 380229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.3121-19C>T		intron_variant	Intron 25 of 26	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.3121-19C>T		intron_variant	Intron 25 of 26	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.328-19C>T		intron_variant	Intron 4 of 9	5		ENSP00000473233.1

Frequencies

GnomAD3 genomes AF: 0.0881 AC: 13392 AN: 152034 Hom.: 1871 Cov.: 34

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0426

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0530

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00403

Gnomad OTH AF: 0.0693

GnomAD2 exomes AF: 0.0307 AC: 6040 AN: 197046 AF XY: 0.0269

Gnomad AFR exome AF: 0.304

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.0236

Gnomad EAS exome AF: 0.000810

Gnomad FIN exome AF: 0.0000611

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0140 AC: 19934 AN: 1428636 Hom.: 1703 Cov.: 33 AF XY: 0.0141 AC XY: 9954 AN XY: 708196

African (AFR) AF: 0.297 AC: 9719 AN: 32774

American (AMR) AF: 0.0212 AC: 849 AN: 40032

Ashkenazi Jewish (ASJ) AF: 0.0247 AC: 631 AN: 25544

East Asian (EAS) AF: 0.000688 AC: 26 AN: 37812

South Asian (SAS) AF: 0.0469 AC: 3869 AN: 82510

European-Finnish (FIN) AF: 0.0000604 AC: 3 AN: 49664

Middle Eastern (MID) AF: 0.0281 AC: 159 AN: 5660

European-Non Finnish (NFE) AF: 0.00278 AC: 3045 AN: 1095596

Other (OTH) AF: 0.0277 AC: 1633 AN: 59044

GnomAD4 genome AF: 0.0884 AC: 13450 AN: 152152 Hom.: 1883 Cov.: 34 AF XY: 0.0866 AC XY: 6444 AN XY: 74408

African (AFR) AF: 0.289 AC: 11997 AN: 41480

American (AMR) AF: 0.0424 AC: 649 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5168

South Asian (SAS) AF: 0.0533 AC: 257 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.00403 AC: 274 AN: 67956

Other (OTH) AF: 0.0733 AC: 155 AN: 2114

Alfa AF: 0.0151 Hom.: 32

Bravo AF: 0.0990

Asia WGS AF: 0.0680 AC: 238 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

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. -

-

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

- -

Nov 02, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 16, 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.3121-19C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2587/33868 control chromosomes (272 homozygotes) at a frequency of 0.0763848, which is approximately 5377 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as benign. -

Colorectal cancer, susceptibility to, 10 Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

May 21, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.6
DANN	Benign	0.92
PhyloP100		-0.33
BranchPoint Hunter		3.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3212330; hg19: chr19-50920410;