rs5744944

chr12-132643245-T-Cchr12-132643245-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006231.4(POLE):c.4530A>G(p.Ala1510=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,612,906 control chromosomes in the GnomAD database, including 178,936 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23127 hom., cov: 34)
  • Exomes 𝑓: 0.46 (155809 hom.)
• Consequence: POLE NM_006231.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.77

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-132643245-T-C is Benign according to our data. Variant chr12-132643245-T-C is described in ClinVar as [Benign]. Clinvar id is 380214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132643245-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.4530A>G	p.Ala1510=	synonymous_variant	35/49	ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.4530A>G	p.Ala1510=	synonymous_variant	35/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81384 AN: 152068 Hom.: 23080 Cov.: 34

Gnomad AFR AF: 0.715

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.701

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.528

GnomAD3 exomes AF: 0.504 AC: 124284 AN: 246480 Hom.: 32733 AF XY: 0.497 AC XY: 66346 AN XY: 133490

Gnomad AFR exome AF: 0.716

Gnomad AMR exome AF: 0.578

Gnomad ASJ exome AF: 0.389

Gnomad EAS exome AF: 0.704

Gnomad SAS exome AF: 0.549

Gnomad FIN exome AF: 0.430

Gnomad NFE exome AF: 0.431

Gnomad OTH exome AF: 0.474

GnomAD4 exome AF: 0.456 AC: 666555 AN: 1460720 Hom.: 155809 Cov.: 42 AF XY: 0.458 AC XY: 333049 AN XY: 726654

Gnomad4 AFR exome AF: 0.716

Gnomad4 AMR exome AF: 0.572

Gnomad4 ASJ exome AF: 0.389

Gnomad4 EAS exome AF: 0.697

Gnomad4 SAS exome AF: 0.546

Gnomad4 FIN exome AF: 0.427

Gnomad4 NFE exome AF: 0.430

Gnomad4 OTH exome AF: 0.471

GnomAD4 genome AF: 0.535 AC: 81479 AN: 152186 Hom.: 23127 Cov.: 34 AF XY: 0.537 AC XY: 39975 AN XY: 74404

Gnomad4 AFR AF: 0.715

Gnomad4 AMR AF: 0.554

Gnomad4 ASJ AF: 0.382

Gnomad4 EAS AF: 0.701

Gnomad4 SAS AF: 0.558

Gnomad4 FIN AF: 0.433

Gnomad4 NFE AF: 0.434

Gnomad4 OTH AF: 0.530

Alfa AF: 0.452 Hom.: 24099

Bravo AF: 0.551

Asia WGS AF: 0.589 AC: 2046 AN: 3478

EpiCase AF: 0.433

EpiControl AF: 0.430

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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 17, 2016	- -
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:3

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 POLE c.4530A>G (p.Ala1510Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 60324/119880 control chromosomes (15839 homozygotes) at a frequency of 0.5032032, which is approximately 35425 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 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. -

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	-0.75
Cadd	Benign	0.020
Dann	Benign	0.34

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: rs5744944; hg19: chr12-133219831; COSMIC: COSV57686501; COSMIC: COSV57686501;