rs3219448

chr19-50417278-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002691.4(POLD1):c.3218+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,568,130 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (11 hom., cov: 34)
  • Exomes 𝑓: 0.0022 (40 hom.)
• Consequence: POLD1 NM_002691.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.591

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-50417278-C-T is Benign according to our data. Variant chr19-50417278-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 439258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50417278-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00742 (1129/152256) while in subpopulation SAS AF= 0.0217 (105/4830). AF 95% confidence interval is 0.0198. There are 11 homozygotes in gnomad4. There are 550 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1123 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.3218+9C>T		intron_variant		ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.3218+9C>T		intron_variant		1	NM_002691.4	P1

Frequencies

GnomAD3 genomes AF: 0.00738 AC: 1123 AN: 152138 Hom.: 11 Cov.: 34

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00498 AC: 998 AN: 200216 Hom.: 10 AF XY: 0.00517 AC XY: 568 AN XY: 109932

Gnomad AFR exome AF: 0.0207

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0191

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000311

Gnomad OTH exome AF: 0.00387

GnomAD4 exome AF: 0.00216 AC: 3054 AN: 1415874 Hom.: 40 Cov.: 31 AF XY: 0.00254 AC XY: 1783 AN XY: 701978

Gnomad4 AFR exome AF: 0.0206

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.0187

Gnomad4 EAS exome AF: 0.0000784

Gnomad4 SAS exome AF: 0.0173

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000102

Gnomad4 OTH exome AF: 0.00521

GnomAD4 genome AF: 0.00742 AC: 1129 AN: 152256 Hom.: 11 Cov.: 34 AF XY: 0.00739 AC XY: 550 AN XY: 74452

Gnomad4 AFR AF: 0.0210

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0217

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00577 Hom.: 1

Bravo AF: 0.00744

Asia WGS AF: 0.0280 AC: 98 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

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	May 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 21, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 13, 2021

- -

Colorectal cancer, susceptibility to, 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2022

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2015

This alteration is classified as likely 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	1.1
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3219448; hg19: chr19-50920535;