rs756417822

Positions:

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

Variant summary

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

The NM_006231.4(POLE):​c.2865-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0425 in 134,162 control chromosomes in the GnomAD database, including 209 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (209 hom., cov: 31)
  • Exomes 𝑓: 0.21 (106 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:9
• 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-GA-G is Benign according to our data. Variant chr12-132661167-GA-G is described in ClinVar as [Likely_benign]. Clinvar id is 695292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132661167-GA-G is described in Lovd as [Benign]. Variant chr12-132661167-GA-G is described in Lovd as [Likely_benign]. Variant chr12-132661167-GA-G is described in Lovd as [Likely_benign]. Variant chr12-132661167-GA-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0425 AC: 5696 AN: 134136 Hom.: 202 Cov.: 31

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0344

Gnomad EAS AF: 0.00194

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0486

Gnomad MID AF: 0.0272

Gnomad NFE AF: 0.0450

Gnomad OTH AF: 0.0334

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.213 AC: 212152 AN: 996606 Hom.: 106 Cov.: 0 AF XY: 0.215 AC XY: 106028 AN XY: 493402

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.334

Gnomad4 ASJ exome AF: 0.224

Gnomad4 EAS exome AF: 0.208

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.0425 AC: 5708 AN: 134162 Hom.: 209 Cov.: 31 AF XY: 0.0447 AC XY: 2886 AN XY: 64570

Gnomad4 AFR AF: 0.0115

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.0344

Gnomad4 EAS AF: 0.00194

Gnomad4 SAS AF: 0.0231

Gnomad4 FIN AF: 0.0486

Gnomad4 NFE AF: 0.0450

Gnomad4 OTH AF: 0.0331

Bravo AF: 0.0420

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2019	- -

Colorectal cancer, susceptibility to, 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2019

- -

Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 17, 2022

- -

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;