rs756417822

Positions:

• chr12-132661167-G-GA
• chr12-132661167-G-GAAAAA
• chr12-132661167-G-GAAAA
• chr12-132661167-G-GAA
• chr12-132661167-GAAA-G
• chr12-132661167-GA-G
• chr12-132661167-GAA-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006231.4(POLE):​c.2865-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 31)
  • Exomes 𝑓: 0.13 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLE NM_006231.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.191

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 -16 ACMG points.

• BP6: Variant 12-132661167-G-GA is Benign according to our data. Variant chr12-132661167-G-GA is described in ClinVar as [Likely_benign]. Clinvar id is 439266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.2865-4dupT		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.2865-4dupT		splice_region_variant, intron_variant		1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 510 AN: 134160 Hom.: 1 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.00798

Gnomad AMI AF: 0.00119

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00868

Gnomad EAS AF: 0.00151

Gnomad SAS AF: 0.00144

Gnomad FIN AF: 0.00634

Gnomad MID AF: 0.00680

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.00452

GnomAD4 exome AF: 0.130 AC: 140309 AN: 1080616 Hom.: 0 Cov.: 0 AF XY: 0.128 AC XY: 68817 AN XY: 537602

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.0749

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.109

Gnomad4 SAS exome AF: 0.135

Gnomad4 FIN exome AF: 0.0876

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.126

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00383 AC: 514 AN: 134184 Hom.: 1 Cov.: 31 AF XY: 0.00370 AC XY: 239 AN XY: 64574

Gnomad4 AFR AF: 0.00804

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00868

Gnomad4 EAS AF: 0.00151

Gnomad4 SAS AF: 0.00144

Gnomad4 FIN AF: 0.00634

Gnomad4 NFE AF: 0.00146

Gnomad4 OTH AF: 0.00448

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 11, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2017

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

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: rs369732588; hg19: chr12-133237753;