chr8-31173019-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PVS1_ModerateBP6BS1BS2

The NM_000553.6(WRN):c.4216C>T(p.Arg1406*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,613,806 control chromosomes in the GnomAD database, including 33 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1406R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 31 hom. )

Consequence

WRN
NM_000553.6 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9O:1

Conservation

PhyloP100: 1.33

Publications

24 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 -7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0193 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BP6

Variant 8-31173019-C-T is Benign according to our data. Variant chr8-31173019-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135443.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00175 (267/152190) while in subpopulation SAS AF = 0.0197 (95/4824). AF 95% confidence interval is 0.0165. There are 2 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6 link	c.4216C>T	p.Arg1406*	stop_gained	Exon 35 of 35	ENST00000298139.7	NP_000544.2	Q14191
WRN	XM_011544639.4 link	c.4135C>T	p.Arg1379*	stop_gained	Exon 34 of 34		XP_011542941.1
WRN	XM_011544640.2 link	c.2617C>T	p.Arg873*	stop_gained	Exon 23 of 23		XP_011542942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7 link	c.4216C>T	p.Arg1406*	stop_gained	Exon 35 of 35	1	NM_000553.6	ENSP00000298139.5		Q14191

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

267

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0197

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00168

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00305

AC:

766

AN:

250856

AF XY:

0.00378

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00141

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00229

AC:

3344

AN:

1461616

Hom.:

Cov.:

AF XY:

0.00274

AC XY:

1991

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33472

American (AMR)

AF:

0.00165

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39648

South Asian (SAS)

AF:

0.0156

AC:

1347

AN:

86252

European-Finnish (FIN)

AF:

0.00114

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00154

AC:

1708

AN:

1111884

Other (OTH)

AF:

0.00214

AC:

129

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

177

354

530

707

884

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.00175

AC:

267

AN:

152190

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

41518

American (AMR)

AF:

0.00170

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.0197

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00168

AC:

114

AN:

68010

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00159

Hom.:

Bravo

AF:

0.00141

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00342

AC:

415

Asia WGS

AF:

0.00867

AC:

AN:

3476

EpiCase

AF:

0.00142

EpiControl

AF:

0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Werner syndrome

Benign:4

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 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

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Uncertain:1Benign:2

May 06, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25619955, 26822949, 27153395, 27667302, 28125075) -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

WRN: BS1, BS2 -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Dec 30, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: WRN c.4216C>T (p.Arg1406X) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been observed or classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.0031 in 250856 control chromosomes, predominantly at a frequency of 0.017 within the South Asian subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in WRN causing Werner Syndrome phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no penetrant association of c.4216C>T in individuals affected with Werner Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as benign/likely benign (n=4)(VUS, n=1). Based on the evidence outlined above, the variant was classified as benign. -

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

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.17

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.35

PhyloP100

1.3

Vest4

0.65

GERP RS

1.9

Mutation Taster

=151/49

polymorphism

(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