rs5745023

Positions:

• chr12-132632300-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000320574.10(POLE):​c.6330+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 1,601,652 control chromosomes in the GnomAD database, including 170,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19553 hom., cov: 32)
  • Exomes 𝑓: 0.45 (151158 hom.)
• Consequence: POLE ENST00000320574.10 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.184

Genes affected

POLE (HGNC:9177): (DNA polymerase epsilon, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-132632300-C-T is Benign according to our data. Variant chr12-132632300-C-T is described in ClinVar as [Benign]. Clinvar id is 380218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132632300-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) 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
POLE	NM_006231.4	c.6330+15G>A		intron_variant		ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.6330+15G>A		intron_variant			XP_011533097.1
POLE	XM_011534797.4	c.5409+15G>A		intron_variant			XP_011533099.1
POLE	XM_011534802.4	c.3318+15G>A		intron_variant			XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6330+15G>A		intron_variant		1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75845 AN: 151806 Hom.: 19538 Cov.: 32

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.701

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.500

GnomAD3 exomes AF: 0.494 AC: 122871 AN: 248930 Hom.: 31412 AF XY: 0.489 AC XY: 65764 AN XY: 134544

Gnomad AFR exome AF: 0.584

Gnomad AMR exome AF: 0.571

Gnomad ASJ exome AF: 0.388

Gnomad EAS exome AF: 0.704

Gnomad SAS exome AF: 0.548

Gnomad FIN exome AF: 0.430

Gnomad NFE exome AF: 0.430

Gnomad OTH exome AF: 0.472

GnomAD4 exome AF: 0.452 AC: 654914 AN: 1449730 Hom.: 151158 Cov.: 30 AF XY: 0.454 AC XY: 327967 AN XY: 721740

Gnomad4 AFR exome AF: 0.582

Gnomad4 AMR exome AF: 0.565

Gnomad4 ASJ exome AF: 0.388

Gnomad4 EAS exome AF: 0.697

Gnomad4 SAS exome AF: 0.546

Gnomad4 FIN exome AF: 0.427

Gnomad4 NFE exome AF: 0.429

Gnomad4 OTH exome AF: 0.460

GnomAD4 genome AF: 0.500 AC: 75892 AN: 151922 Hom.: 19553 Cov.: 32 AF XY: 0.502 AC XY: 37291 AN XY: 74268

Gnomad4 AFR AF: 0.590

Gnomad4 AMR AF: 0.543

Gnomad4 ASJ AF: 0.381

Gnomad4 EAS AF: 0.701

Gnomad4 SAS AF: 0.558

Gnomad4 FIN AF: 0.433

Gnomad4 NFE AF: 0.434

Gnomad4 OTH AF: 0.502

Alfa AF: 0.452 Hom.: 2939

Bravo AF: 0.510

Asia WGS AF: 0.578 AC: 2008 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 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	PreventionGenetics, part of Exact Sciences	Oct 03, 2016	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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: c.6330+15G>A in POLE gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 49% (58808/119032 chrs tested), including numerous homozygous occurrences. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.0014%, suggesting that it is a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals or cited by reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Colorectal cancer, susceptibility to, 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Facial dysmorphism-immunodeficiency-livedo-short stature syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.59
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs5745023; hg19: chr12-133208886;