rs5744777

chr12-132673167-G-Achr12-132673167-G-Cchr12-132673167-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006231.4(POLE):c.1470C>T(p.Asp490=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,595,862 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (7 hom.)
• Consequence: POLE NM_006231.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.307

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=-0.54).
• BP6: Variant 12-132673167-G-A is Benign according to our data. Variant chr12-132673167-G-A is described in ClinVar as [Benign]. Clinvar id is 220802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132673167-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.307 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00613 (933/152326) while in subpopulation AFR AF= 0.0208 (863/41570). AF 95% confidence interval is 0.0196. There are 9 homozygotes in gnomad4. There are 458 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.1470C>T	p.Asp490=	synonymous_variant	14/49	ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.1470C>T	p.Asp490=	synonymous_variant	14/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 934 AN: 152208 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00176 AC: 443 AN: 251416 Hom.: 2 AF XY: 0.00135 AC XY: 183 AN XY: 135864

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000740 AC: 1068 AN: 1443536 Hom.: 7 Cov.: 30 AF XY: 0.000678 AC XY: 488 AN XY: 719294

Gnomad4 AFR exome AF: 0.0211

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000191

Gnomad4 OTH exome AF: 0.00135

GnomAD4 genome AF: 0.00613 AC: 933 AN: 152326 Hom.: 9 Cov.: 33 AF XY: 0.00615 AC XY: 458 AN XY: 74480

Gnomad4 AFR AF: 0.0208

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00328 Hom.: 3

Bravo AF: 0.00696

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 02, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 22, 2018	- -

Colorectal cancer, susceptibility to, 12 Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 19, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	This variant is associated with the following publications: (PMID: 25224212) -

Carcinoma of colon Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLE p.Asp490= variant was identified in the literature as a polymorphism in 8 of 544 endometrial tumours (Billingsley 2015). The variant was also identified in dbSNP (ID: rs5744777) as “With Likely benign allele” and in ClinVar (classified benign by Invitae, Ambry Genetics, Counsyl, Prevention Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano; and likely benign by GeneDx). The variant was identified in control databases in 596 (5 homozygous) of 277152 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Tche variant was observed in the following populations: African in 511 of 24034 chromosomes (freq: 0.02), Other in 2 of 6466 chromosomes (freq: 0.0003), Latino in 37 of 34420 chromosomes (freq: 0.001), European Non-Finnish in 43 of 126646 chromosomes (freq: 0.0003), and South Asian in 3 of 30782 chromosomes (freq: 0.0001) while not observed in the Ashkenazi Jewish, East Asian and Finnish populations. The p.Asp490= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs 4 nucleotides from the end of exon 14 and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	1.8
Dann	Benign	0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs5744777; hg19: chr12-133249753;