19-50415712-A-G

Position:

• chr19-50415712-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 380221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50415712-A-G is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.2718-12A>G		intron_variant		ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.2718-12A>G		intron_variant		1	NM_002691.4	ENSP00000406046.1

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

GnomAD3 exomes AF: 0.172 AC: 20282 AN: 118132 Hom.: 2429 AF XY: 0.173 AC XY: 11144 AN XY: 64506

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 SAS exome AF: 0.278

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

Gnomad4 AFR exome AF: 0.602

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.205

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.282

Gnomad4 FIN exome AF: 0.0834

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.198

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

Gnomad4 AFR AF: 0.657

Gnomad4 AMR AF: 0.385

Gnomad4 ASJ AF: 0.386

Gnomad4 EAS AF: 0.402

Gnomad4 SAS AF: 0.484

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.268

Gnomad4 OTH AF: 0.455

Alfa AF: 0.0976 Hom.: 376

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

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 02, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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.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. -

Mandibular hypoplasia-deafness-progeroid syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Colorectal cancer, susceptibility to, 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.46
DANN	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs3219433; hg19: chr19-50918969;