8-31167138-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000553.6(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. 14/21 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. C1367Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.23 ( 4075 hom., cov: 32)

Exomes 𝑓: 0.25 ( 46716 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: 0.253

Publications

120 publications found

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 Gene-Disease associations (from GenCC):

Werner syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
osteosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

WRN links:

ENSG00000253961 (HGNC:58431):

ENSG00000253961 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 130762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
WRN	NM_000553.6 link	c.4099T>C	p.Cys1367Arg	missense_variant	Exon 34 of 35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7 link	c.4099T>C	p.Cys1367Arg	missense_variant	Exon 34 of 35	1	NM_000553.6	ENSP00000298139.5

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

GnomAD2 exomes

AF:

0.238

AC:

59621

AN:

250952

AF XY:

0.242

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 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

African (AFR)

AF:

0.161

AC:

5390

AN:

33450

American (AMR)

AF:

0.195

AC:

8707

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.207

AC:

5419

AN:

26118

East Asian (EAS)

AF:

0.0893

AC:

3543

AN:

39666

South Asian (SAS)

AF:

0.277

AC:

23911

AN:

86228

European-Finnish (FIN)

AF:

0.293

AC:

15655

AN:

53390

Middle Eastern (MID)

AF:

0.234

AC:

1348

AN:

5766

European-Non Finnish (NFE)

AF:

0.257

AC:

285131

AN:

1111446

Other (OTH)

AF:

0.239

AC:

14397

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

15109

30217

45326

60434

75543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9456

18912

28368

37824

47280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.226

AC:

34282

AN:

152006

Hom.:

4075

Cov.:

AF XY:

0.226

AC XY:

16763

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.163

AC:

6766

AN:

41492

American (AMR)

AF:

0.197

AC:

3009

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.201

AC:

697

AN:

3470

East Asian (EAS)

AF:

0.114

AC:

586

AN:

5162

South Asian (SAS)

AF:

0.288

AC:

1387

AN:

4820

European-Finnish (FIN)

AF:

0.296

AC:

3126

AN:

10568

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.265

AC:

18007

AN:

67936

Other (OTH)

AF:

0.223

AC:

472

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1353

2705

4058

5410

6763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

370

740

1110

1480

1850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.245

Hom.:

23108

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:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6Other:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Oct 14, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Werner syndrome

Benign:5

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

May 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Wiskott-Aldrich syndrome

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

0.25

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

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over