chr8-31167138-T-C

Position:

chr8-31167138-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000298139.7(WRN):c.4099T>C(p.Cys1367Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,613,060 control chromosomes in the GnomAD database, including 50,791 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1367H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.23 ( 4075 hom., cov: 32)

Exomes 𝑓: 0.25 ( 46716 hom. )

Consequence

WRN
ENST00000298139.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 0.253

Variant links:

Genes affected

WRN (HGNC:12791): (WRN RecQ like helicase) This gene encodes a member of the RecQ subfamily of DNA helicase proteins. The encoded nuclear protein is important in the maintenance of genome stability and plays a role in DNA repair, replication, transcription and telomere maintenance. This protein contains a N-terminal 3' to 5' exonuclease domain, an ATP-dependent helicase domain and RQC (RecQ helicase conserved region) domain in its central region, and a C-terminal HRDC (helicase RNase D C-terminal) domain and nuclear localization signal. Defects in this gene are the cause of Werner syndrome, an autosomal recessive disorder characterized by accelerated aging and an elevated risk for certain cancers. [provided by RefSeq, Aug 2017]

WRN links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015725493).

BP6

Variant 8-31167138-T-C is Benign according to our data. Variant chr8-31167138-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 130762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-31167138-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6 linkuse as main transcript	c.4099T>C	p.Cys1367Arg	missense_variant	34/35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7 linkuse as main transcript	c.4099T>C	p.Cys1367Arg	missense_variant	34/35	1	NM_000553.6	ENSP00000298139	P1
	ENST00000521252.1 linkuse as main transcript	n.236A>G		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34263

AN:

151888

Hom.:

4073

Cov.:

show subpopulations

Gnomad AFR

AF:

0.163

Gnomad AMI

AF:

0.186

Gnomad AMR

AF:

0.197

Gnomad ASJ

AF:

0.201

Gnomad EAS

AF:

0.114

Gnomad SAS

AF:

0.287

Gnomad FIN

AF:

0.296

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.265

Gnomad OTH

AF:

0.223

GnomAD3 exomes

AF:

0.238

AC:

59621

AN:

250952

Hom.:

7516

AF XY:

0.242

AC XY:

32811

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.162

Gnomad AMR exome

AF:

0.191

Gnomad ASJ exome

AF:

0.206

Gnomad EAS exome

AF:

0.113

Gnomad SAS exome

AF:

0.278

Gnomad FIN exome

AF:

0.289

Gnomad NFE exome

AF:

0.264

Gnomad OTH exome

AF:

0.246

GnomAD4 exome

AF:

0.249

AC:

363501

AN:

1461054

Hom.:

46716

Cov.:

AF XY:

0.250

AC XY:

182066

AN XY:

726832

show subpopulations

Gnomad4 AFR exome

AF:

0.161

Gnomad4 AMR exome

AF:

0.195

Gnomad4 ASJ exome

AF:

0.207

Gnomad4 EAS exome

AF:

0.0893

Gnomad4 SAS exome

AF:

0.277

Gnomad4 FIN exome

AF:

0.293

Gnomad4 NFE exome

AF:

0.257

Gnomad4 OTH exome

AF:

0.239

GnomAD4 genome

AF:

0.226

AC:

34282

AN:

152006

Hom.:

4075

Cov.:

AF XY:

0.226

AC XY:

16763

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.163

Gnomad4 AMR

AF:

0.197

Gnomad4 ASJ

AF:

0.201

Gnomad4 EAS

AF:

0.114

Gnomad4 SAS

AF:

0.288

Gnomad4 FIN

AF:

0.296

Gnomad4 NFE

AF:

0.265

Gnomad4 OTH

AF:

0.223

Alfa

AF:

0.247

Hom.:

12233

Bravo

AF:

0.211

TwinsUK

AF:

0.249

AC:

922

ALSPAC

AF:

0.250

AC:

964

ESP6500AA

AF:

0.172

AC:

757

ESP6500EA

AF:

0.256

AC:

2200

ExAC

AF:

0.241

AC:

29284

Asia WGS

AF:

0.182

AC:

633

AN:

3478

EpiCase

AF:

0.259

EpiControl

AF:

0.252

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6Other:1

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Werner syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2018	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. -

Wiskott-Aldrich syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.29

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

MutationTaster

Benign

0.055

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.070

Sift

Benign

0.035

Sift4G

Benign

0.095

Polyphen

0.74

Vest4

0.12

MPC

0.21

ClinPred

0.014

GERP RS

2.5

Varity_R

0.37

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over