rs3218767

Positions:

• chr19-50409679-G-GA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002691.4(POLD1):​c.2154+13_2154+14insA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 1,588,032 control chromosomes in the GnomAD database, including 176 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (82 hom.)
• Consequence: POLD1 NM_002691.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.12

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 19-50409679-G-GA is Benign according to our data. Variant chr19-50409679-G-GA is described in ClinVar as [Benign]. Clinvar id is 419831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.2154+13_2154+14insA		intron_variant		ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.2154+13_2154+14insA		intron_variant		1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2900 AN: 152234 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.00519 AC: 1214 AN: 234120 Hom.: 40 AF XY: 0.00372 AC XY: 474 AN XY: 127308

Gnomad AFR exome AF: 0.0675

Gnomad AMR exome AF: 0.00460

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000357

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00185 AC: 2662 AN: 1435680 Hom.: 82 Cov.: 32 AF XY: 0.00159 AC XY: 1127 AN XY: 710336

Gnomad4 AFR exome AF: 0.0638

Gnomad4 AMR exome AF: 0.00501

Gnomad4 ASJ exome AF: 0.0000797

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000155

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000867

Gnomad4 OTH exome AF: 0.00400

GnomAD4 genome AF: 0.0191 AC: 2906 AN: 152352 Hom.: 94 Cov.: 32 AF XY: 0.0183 AC XY: 1365 AN XY: 74494

Gnomad4 AFR AF: 0.0658

Gnomad4 AMR AF: 0.00777

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00731 Hom.: 5

Bravo AF: 0.0217

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 19, 2016	Variant summary: The POLD1 c.2154+13_2154+14insA variant involves the insertion of an 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. However, these predictions have yet to be confirmed by functional studies. This variant was found in 686/112178 control chromosomes (26 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0667447 (627/9394). This frequency is about 4699 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 06, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Carcinoma of colon Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLD1 c.2154+13_2154+14insA variant was not identified in the literature nor was it identified in MutDB. The variant was identified in dbSNP (ID: rs3218767 as With Benign allele) and ClinVar (2x as benign). The variant was identified in control databases in 1751 of 261160 chromosomes (64 homozygous) at a frequency of 0.007 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 1563 of 23566 chromosomes (freq: 0.07), Latino in 153 of 32366 chromosomes (freq: 0.005), Other in 13 of 6046 chromosomes (freq: 0.002), European Non-Finnish in 20 of 118628 chromosomes (freq: 0.0002), Ashkenazi Jewish in 1 of 8814 chromosomes (freq: 0.0001), South Asian in 1 of 28168 chromosomes (freq: 0.00004), while the variant was not observed in the East Asian or Finnish populations. The variant occurs outside of the splicing consensus sequence and 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. -

Colorectal cancer, susceptibility to, 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2015

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

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs3218767; hg19: chr19-50912936;