chr12-132657119-T-C

Position:

• chr12-132657119-T-C

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.3582+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.964 in 1,613,426 control chromosomes in the GnomAD database, including 750,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (72246 hom., cov: 29)
  • Exomes 𝑓: 0.96 (678149 hom.)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.11

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=-0.95).
• BP6: Variant 12-132657119-T-C is Benign according to our data. Variant chr12-132657119-T-C is described in ClinVar as [Benign]. Clinvar id is 380211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132657119-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.3582+17A>G		intron_variant		ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.3582+17A>G		intron_variant		1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.975 AC: 148139 AN: 152010 Hom.: 72185 Cov.: 29

Gnomad AFR AF: 0.993

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.973

Gnomad ASJ AF: 0.984

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.972

Gnomad FIN AF: 0.965

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.963

Gnomad OTH AF: 0.968

GnomAD3 exomes AF: 0.971 AC: 243962 AN: 251156 Hom.: 118511 AF XY: 0.971 AC XY: 131790 AN XY: 135750

Gnomad AFR exome AF: 0.993

Gnomad AMR exome AF: 0.974

Gnomad ASJ exome AF: 0.982

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.966

Gnomad FIN exome AF: 0.964

Gnomad NFE exome AF: 0.965

Gnomad OTH exome AF: 0.971

GnomAD4 exome AF: 0.963 AC: 1407674 AN: 1461298 Hom.: 678149 Cov.: 45 AF XY: 0.964 AC XY: 700595 AN XY: 726938

Gnomad4 AFR exome AF: 0.994

Gnomad4 AMR exome AF: 0.974

Gnomad4 ASJ exome AF: 0.984

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.965

Gnomad4 FIN exome AF: 0.963

Gnomad4 NFE exome AF: 0.960

Gnomad4 OTH exome AF: 0.968

GnomAD4 genome AF: 0.975 AC: 148259 AN: 152128 Hom.: 72246 Cov.: 29 AF XY: 0.975 AC XY: 72472 AN XY: 74348

Gnomad4 AFR AF: 0.993

Gnomad4 AMR AF: 0.973

Gnomad4 ASJ AF: 0.984

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.972

Gnomad4 FIN AF: 0.965

Gnomad4 NFE AF: 0.963

Gnomad4 OTH AF: 0.969

Alfa AF: 0.973 Hom.: 13367

Bravo AF: 0.976

Asia WGS AF: 0.986 AC: 3428 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

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, 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. -

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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.3582+17A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 117844/121342 control chromosomes (57239 homozygotes) at a frequency of 0.9711724, which is approximately 68370 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), indicating this variant is the common allele and a benign polymorphism. Taken together, this variant is classified as benign. -

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

Jun 03, 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	-0.95
CADD	Benign	0.30
DANN	Benign	0.31
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: rs5744889; hg19: chr12-133233705;