chr19-50416540-C-T

Position:

chr19-50416540-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002691.4(POLD1):c.2953+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 1,549,824 control chromosomes in the GnomAD database, including 327,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 25596 hom., cov: 34)

Exomes 𝑓: 0.65 ( 301641 hom. )

Consequence

POLD1
NM_002691.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.631

Variant links:

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 links:

ENSG00000142539 (HGNC:):

ENSG00000142539 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 19-50416540-C-T is Benign according to our data. Variant chr19-50416540-C-T is described in ClinVar as [Benign]. Clinvar id is 258788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50416540-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.2953+12C>T		intron_variant		ENST00000440232.7	NP_002682.2	P28340A0A024R4F4Q59FA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7 linkuse as main transcript	c.2953+12C>T		intron_variant		1	NM_002691.4	ENSP00000406046.1		P28340
ENSG00000142539	ENST00000599632.1 linkuse as main transcript	c.160+12C>T		intron_variant		5		ENSP00000473233.1		M0R3H8

Frequencies

GnomAD3 genomes

AF:

0.552

AC:

83965

AN:

152096

Hom.:

25590

Cov.:

show subpopulations

Gnomad AFR

AF:

0.329

Gnomad AMI

AF:

0.598

Gnomad AMR

AF:

0.643

Gnomad ASJ

AF:

0.509

Gnomad EAS

AF:

0.140

Gnomad SAS

AF:

0.439

Gnomad FIN

AF:

0.692

Gnomad MID

AF:

0.566

Gnomad NFE

AF:

0.687

Gnomad OTH

AF:

0.540

GnomAD3 exomes

AF:

0.582

AC:

89666

AN:

154134

Hom.:

28435

AF XY:

0.574

AC XY:

47665

AN XY:

83086

show subpopulations

Gnomad AFR exome

AF:

0.327

Gnomad AMR exome

AF:

0.702

Gnomad ASJ exome

AF:

0.516

Gnomad EAS exome

AF:

0.136

Gnomad SAS exome

AF:

0.449

Gnomad FIN exome

AF:

0.685

Gnomad NFE exome

AF:

0.686

Gnomad OTH exome

AF:

0.610

GnomAD4 exome

AF:

0.645

AC:

901856

AN:

1397608

Hom.:

301641

Cov.:

AF XY:

0.640

AC XY:

441424

AN XY:

690068

show subpopulations

Gnomad4 AFR exome

AF:

0.320

Gnomad4 AMR exome

AF:

0.697

Gnomad4 ASJ exome

AF:

0.514

Gnomad4 EAS exome

AF:

0.117

Gnomad4 SAS exome

AF:

0.453

Gnomad4 FIN exome

AF:

0.687

Gnomad4 NFE exome

AF:

0.690

Gnomad4 OTH exome

AF:

0.591

GnomAD4 genome

AF:

0.552

AC:

83985

AN:

152216

Hom.:

25596

Cov.:

AF XY:

0.550

AC XY:

40943

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.328

Gnomad4 AMR

AF:

0.643

Gnomad4 ASJ

AF:

0.509

Gnomad4 EAS

AF:

0.140

Gnomad4 SAS

AF:

0.439

Gnomad4 FIN

AF:

0.692

Gnomad4 NFE

AF:

0.687

Gnomad4 OTH

AF:

0.535

Alfa

AF:

0.610

Hom.:

5292

Bravo

AF:

0.539

Asia WGS

AF:

0.301

AC:

1051

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 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 86% of patients studied by a panel of primary immunodeficiencies. Number of patients: 82. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
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.2953+12C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant, and 5/5 Alamut algorithms predict not significant change to splicing. This variant was found in 13998/24162 control chromosomes (4157 homozygotes) at a frequency of 0.5793395, which is approximately 40785 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), highly suggesting this variant is a benign polymorphism. 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. -

Colorectal cancer, susceptibility to, 10

Benign:2

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

Mandibular hypoplasia-deafness-progeroid syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

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

-0.86

CADD

Benign

2.9

DANN

Benign

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over