NM_002691.4:c.2718-12A>G

Variant names:

• chr19-50415712-A-G
• rs3219433
• NM_002691.4:c.2718-12A>G

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.2718-12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 970,990 control chromosomes in the GnomAD database, including 18,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (6299 hom., cov: 0)
  • Exomes 𝑓: 0.15 (11732 hom.)
• Consequence: POLD1 NM_002691.4 intron
• Scores: Splicing: ADA: 0.00003785
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.90
• Publications: 10 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: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-50415712-A-G is Benign according to our data. Variant chr19-50415712-A-G is described in ClinVar as Benign. ClinVar VariationId is 380221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.2718-12A>G		intron_variant	Intron 21 of 26	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.2718-12A>G		intron_variant	Intron 21 of 26	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.-88A>G		upstream_gene_variant		5		ENSP00000473233.1

Frequencies

GnomAD3 genomes AF: 0.490 AC: 30979 AN: 63262 Hom.: 6263 Cov.: 0

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.461

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.452

GnomAD2 exomes AF: 0.172 AC: 20282 AN: 118132 AF XY: 0.173

Gnomad AFR exome AF: 0.573

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.0414

Gnomad NFE exome AF: 0.0882

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.149 AC: 135388 AN: 907598 Hom.: 11732 Cov.: 30 AF XY: 0.153 AC XY: 69181 AN XY: 452266

African (AFR) AF: 0.602 AC: 17454 AN: 28978

American (AMR) AF: 0.158 AC: 4389 AN: 27770

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 3290 AN: 16052

East Asian (EAS) AF: 0.310 AC: 6031 AN: 19476

South Asian (SAS) AF: 0.282 AC: 18892 AN: 66930

European-Finnish (FIN) AF: 0.0834 AC: 1607 AN: 19266

Middle Eastern (MID) AF: 0.249 AC: 652 AN: 2620

European-Non Finnish (NFE) AF: 0.110 AC: 75908 AN: 690286

Other (OTH) AF: 0.198 AC: 7165 AN: 36220

GnomAD4 genome AF: 0.490 AC: 31071 AN: 63392 Hom.: 6299 Cov.: 0 AF XY: 0.483 AC XY: 14916 AN XY: 30904

African (AFR) AF: 0.657 AC: 21058 AN: 32060

American (AMR) AF: 0.385 AC: 2079 AN: 5396

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 473 AN: 1224

East Asian (EAS) AF: 0.402 AC: 726 AN: 1806

South Asian (SAS) AF: 0.484 AC: 1146 AN: 2366

European-Finnish (FIN) AF: 0.189 AC: 365 AN: 1934

Middle Eastern (MID) AF: 0.404 AC: 46 AN: 114

European-Non Finnish (NFE) AF: 0.268 AC: 4647 AN: 17328

Other (OTH) AF: 0.455 AC: 401 AN: 882

Alfa AF: 0.115 Hom.: 488

Bravo AF: 0.235

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Nov 02, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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 24% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -

Nov 08, 2017

Genetic Services Laboratory, University of Chicago

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.2718-12A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 3998/15036 control chromosomes (617 homozygotes) at a frequency of 0.2658952, which is approximately 18719 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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

Colorectal cancer, susceptibility to, 10 Benign:1

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: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	-0.89
CADD	Benign	0.46
DANN	Benign	0.61
PhyloP100		-1.9
PromoterAI		-0.0054	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0040
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: rs3219433; hg19: chr19-50918969;