rs571641918

Positions:

• chr12-132642486-A-AACG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000320574.10(POLE):​c.4952+19_4952+20insCGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00818 in 1,607,440 control chromosomes in the GnomAD database, including 70 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0085 (65 hom.)
• Consequence: POLE ENST00000320574.10 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.00100

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 -16 ACMG points.

• BP6: Variant 12-132642486-A-AACG is Benign according to our data. Variant chr12-132642486-A-AACG is described in ClinVar as [Likely_benign]. Clinvar id is 371873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00533 (811/152200) while in subpopulation NFE AF= 0.00893 (607/67980). AF 95% confidence interval is 0.00834. There are 5 homozygotes in gnomad4. There are 383 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.4952+19_4952+20insCGT		intron_variant		ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.4952+19_4952+20insCGT		intron_variant		1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes AF: 0.00533 AC: 811 AN: 152082 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00434

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00893

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00565 AC: 1407 AN: 249166 Hom.: 7 AF XY: 0.00564 AC XY: 760 AN XY: 134830

Gnomad AFR exome AF: 0.000989

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.00787

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00374

Gnomad NFE exome AF: 0.00987

Gnomad OTH exome AF: 0.00541

GnomAD4 exome AF: 0.00848 AC: 12335 AN: 1455240 Hom.: 65 Cov.: 34 AF XY: 0.00817 AC XY: 5908 AN XY: 722832

Gnomad4 AFR exome AF: 0.000839

Gnomad4 AMR exome AF: 0.00258

Gnomad4 ASJ exome AF: 0.00710

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00479

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.00619

GnomAD4 genome AF: 0.00533 AC: 811 AN: 152200 Hom.: 5 Cov.: 33 AF XY: 0.00515 AC XY: 383 AN XY: 74384

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00434

Gnomad4 NFE AF: 0.00893

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00714 Hom.: 0

Bravo AF: 0.00532

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 20, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2017	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:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Oct 03, 2023	- -

Colorectal cancer, susceptibility to, 12 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Jul 05, 2016

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2015

This alteration is classified as likely 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs571641918; hg19: chr12-133219072;