rs5744941

Positions:

• chr12-132643403-A-T

Variant summary

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

The NM_006231.4(POLE):​c.4444+4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0763 in 1,614,164 control chromosomes in the GnomAD database, including 5,271 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (329 hom., cov: 34)
  • Exomes 𝑓: 0.078 (4942 hom.)
• Consequence: POLE NM_006231.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002649
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.304

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]

POLE (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 12-132643403-A-T is Benign according to our data. Variant chr12-132643403-A-T is described in ClinVar as [Benign]. Clinvar id is 380213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132643403-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.4444+4T>A		splice_region_variant, intron_variant		ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.4444+4T>A		splice_region_variant, intron_variant		1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.0563 AC: 8564 AN: 152194 Hom.: 328 Cov.: 34

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.0357

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.0745

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.0658

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0822

Gnomad OTH AF: 0.0488

GnomAD3 exomes AF: 0.0624 AC: 15693 AN: 251402 Hom.: 585 AF XY: 0.0631 AC XY: 8567 AN XY: 135876

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.0305

Gnomad ASJ exome AF: 0.0970

Gnomad EAS exome AF: 0.0749

Gnomad SAS exome AF: 0.0306

Gnomad FIN exome AF: 0.0669

Gnomad NFE exome AF: 0.0813

Gnomad OTH exome AF: 0.0762

GnomAD4 exome AF: 0.0784 AC: 114555 AN: 1461852 Hom.: 4942 Cov.: 37 AF XY: 0.0769 AC XY: 55936 AN XY: 727232

Gnomad4 AFR exome AF: 0.0117

Gnomad4 AMR exome AF: 0.0308

Gnomad4 ASJ exome AF: 0.0952

Gnomad4 EAS exome AF: 0.0798

Gnomad4 SAS exome AF: 0.0316

Gnomad4 FIN exome AF: 0.0666

Gnomad4 NFE exome AF: 0.0862

Gnomad4 OTH exome AF: 0.0780

GnomAD4 genome AF: 0.0562 AC: 8561 AN: 152312 Hom.: 329 Cov.: 34 AF XY: 0.0545 AC XY: 4059 AN XY: 74480

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.0357

Gnomad4 ASJ AF: 0.0968

Gnomad4 EAS AF: 0.0741

Gnomad4 SAS AF: 0.0313

Gnomad4 FIN AF: 0.0658

Gnomad4 NFE AF: 0.0822

Gnomad4 OTH AF: 0.0497

Alfa AF: 0.0755 Hom.: 152

Bravo AF: 0.0542

Asia WGS AF: 0.0610 AC: 214 AN: 3478

EpiCase AF: 0.0785

EpiControl AF: 0.0792

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 03, 2016	- -
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, 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	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 19, 2016	Variant summary: c.4444+4T>A in POLE gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant enhances the donor cite, 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 0.0624 (7579/121388 chrs tested), predominantly in individuals of European descent (0.0819; 5568/66728 chrs tested) including numerous homozygous occurrences. The observed frequencies exceed 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 in published reports or cited by reputable databases/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 19, 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. -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Mar 02, 2018	- -

Colorectal cancer, susceptibility to, 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.5
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0060
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: rs5744941; hg19: chr12-133219989;