19-50417279-A-G

Position:

• chr19-50417279-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.3218+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0248 in 1,568,710 control chromosomes in the GnomAD database, including 5,179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2751 hom., cov: 34)
  • Exomes 𝑓: 0.016 (2428 hom.)
• Consequence: POLD1 NM_002691.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.73

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]

ENSG00000142539 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 19-50417279-A-G is Benign according to our data. Variant chr19-50417279-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 371933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50417279-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.3218+10A>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.3218+10A>G		intron_variant		1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.425+10A>G		intron_variant		5		ENSP00000473233.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16211 AN: 152008 Hom.: 2731 Cov.: 34

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0517

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.00328

Gnomad SAS AF: 0.0572

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.0866

GnomAD3 exomes AF: 0.0353 AC: 7078 AN: 200644 Hom.: 820 AF XY: 0.0299 AC XY: 3298 AN XY: 110150

Gnomad AFR exome AF: 0.362

Gnomad AMR exome AF: 0.0230

Gnomad ASJ exome AF: 0.0259

Gnomad EAS exome AF: 0.00185

Gnomad SAS exome AF: 0.0466

Gnomad FIN exome AF: 0.0000946

Gnomad NFE exome AF: 0.00413

Gnomad OTH exome AF: 0.0240

GnomAD4 exome AF: 0.0160 AC: 22680 AN: 1416584 Hom.: 2428 Cov.: 31 AF XY: 0.0159 AC XY: 11142 AN XY: 702196

Gnomad4 AFR exome AF: 0.361

Gnomad4 AMR exome AF: 0.0254

Gnomad4 ASJ exome AF: 0.0268

Gnomad4 EAS exome AF: 0.00117

Gnomad4 SAS exome AF: 0.0477

Gnomad4 FIN exome AF: 0.0000730

Gnomad4 NFE exome AF: 0.00283

Gnomad4 OTH exome AF: 0.0327

GnomAD4 genome AF: 0.107 AC: 16288 AN: 152126 Hom.: 2751 Cov.: 34 AF XY: 0.104 AC XY: 7744 AN XY: 74386

Gnomad4 AFR AF: 0.352

Gnomad4 AMR AF: 0.0515

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.00329

Gnomad4 SAS AF: 0.0576

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00419

Gnomad4 OTH AF: 0.0904

Alfa AF: 0.0440 Hom.: 333

Bravo AF: 0.121

Asia WGS AF: 0.0810 AC: 282 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 02, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 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, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Colorectal cancer, susceptibility to, 10 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Aug 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:2

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.3218+10A>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 3172/55760 control chromosomes (370 homozygotes) at a frequency of 0.0568867, which is approximately 4005 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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.93
CADD	Benign	0.96
DANN	Benign	0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2463239; hg19: chr19-50920536;