8-31096778-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_000553.6(WRN):c.1909C>T(p.Arg637Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,609,108 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R637L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1O:1

Conservation

PhyloP100: 1.43

Publications

13 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000372 (543/1459272) while in subpopulation MID AF = 0.00399 (23/5764). AF 95% confidence interval is 0.00273. There are 1 homozygotes in GnomAdExome4. There are 271 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000553.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	NM_000553.6	MANE Select	c.1909C>T	p.Arg637Trp	missense	Exon 17 of 35	NP_000544.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WRN	ENST00000298139.7	TSL:1 MANE Select	c.1909C>T	p.Arg637Trp	missense	Exon 17 of 35	ENSP00000298139.5
WRN	ENST00000521620.5	TSL:1	n.542C>T		non_coding_transcript_exon	Exon 5 of 23
WRN	ENST00000650667.1		n.*1523C>T		non_coding_transcript_exon	Exon 16 of 34	ENSP00000498593.1

Frequencies

GnomAD3 genomes

AF:

0.000321

AC:

AN:

149736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000400

Gnomad ASJ

AF:

0.000578

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000576

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000412

AC:

103

AN:

249788

AF XY:

0.000392

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000464

Gnomad ASJ exome

AF:

0.000597

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000662

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000372

AC:

543

AN:

1459272

Hom.:

Cov.:

AF XY:

0.000373

AC XY:

271

AN XY:

726072

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33436

American (AMR)

AF:

0.000515

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.000728

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39626

South Asian (SAS)

AF:

0.000174

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.0000579

AC:

AN:

51826

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000380

AC:

422

AN:

1111288

Other (OTH)

AF:

0.000497

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000327

AC:

AN:

149836

Hom.:

Cov.:

AF XY:

0.000316

AC XY:

AN XY:

72888

show subpopulations

African (AFR)

AF:

0.0000490

AC:

AN:

40812

American (AMR)

AF:

0.000399

AC:

AN:

15022

Ashkenazi Jewish (ASJ)

AF:

0.000578

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5100

South Asian (SAS)

AF:

0.00

AC:

AN:

4744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9758

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000576

AC:

AN:

67666

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000573

Hom.:

Bravo

AF:

0.000476

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000362

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.000927

EpiControl

AF:

0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Werner syndrome

Uncertain:2Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Jan 23, 2024

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:2

Jan 27, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The WRN p.Arg637Trp variant was identified in 1 of 18 Werner syndrome patients; the variant was identified as a compound heterozygous mutation in a male with Werner syndrome, osteoporosis and cancer (Uhrhammer_2006_PMID:16786514). The variant was identified in dbSNP (ID: rs148286708) and ClinVar (classified as uncertain significance by EGL Genetic Diagnotics and Invitae) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 111 of 279850 chromosomes (0 homozygous) at a frequency of 0.0003966 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 7 of 10332 chromosomes (freq: 0.000678), European (non-Finnish) in 79 of 128100 chromosomes (freq: 0.000617), Other in 4 of 7152 chromosomes (freq: 0.000559), Latino in 17 of 35294 chromosomes (freq: 0.000482), South Asian in 3 of 30544 chromosomes (freq: 0.000098) and European (Finnish) in 1 of 23934 chromosomes (freq: 0.000042), but was not observed in the African or East Asian populations. The p.Arg637 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

not specified

Uncertain:1Other:1

Jun 15, 2021

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the WRN gene demonstrated a sequence change, c.1909C>T, in exon 17 that results in an amino acid change, p.Arg637Trp. This sequence change has been described in gnomAD with a frequency of 0.062% in Non-Finnish European sub-population (dbSNP rs148286708). The p.Arg637Trp change affects a highly conserved amino acid residue located in a domain of the WRN protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg637Trp substitution. This particular sequence change has been reported in the compound heterozygous state in one individual with Werner syndrome, osteoporosis, and cancer (PMID: 16786514). Due to the lack of sufficient evidences, the clinical significance of the p.Arg637Trp change remains unknown at this time.

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

WRN-related disorder

Uncertain:1

Dec 19, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The WRN c.1909C>T variant is predicted to result in the amino acid substitution p.Arg637Trp. This variant was reported in the compound heterozygous state in an individual with Werner syndrome; however no functional or family segregation studies have confirmed its pathogenicity (Patient 943-1, Uhrhammer et al. 2006. PubMed ID: 16786514). This variant was also reported in an individual with head and neck cancer (Table S3, Cury et al. 2021. PubMed ID: 34598035) and an individual with osteosarcoma (eTable 5, Mirabello et al. 2020. PubMed ID: 32191290). This variant is reported in 0.068% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. In ClinVar, this variant has conflicting interpretations of pathogenicity ranging from benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/135421). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.81

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.4

PhyloP100

1.4

PrimateAI

Benign

0.25

PROVEAN

Pathogenic

-6.8

REVEL

Benign

0.18

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.71

MVP

0.65

MPC

0.40

ClinPred

0.21

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.71

gMVP

0.80

Mutation Taster

=28/72

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over