rs4987239

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.355+20A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,612,694 control chromosomes in the GnomAD database, including 2,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 184 hom., cov: 33)

Exomes 𝑓: 0.058 ( 2742 hom. )

Consequence

WRN
NM_000553.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.140

Publications

4 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 8-31064454-A-T is Benign according to our data. Variant chr8-31064454-A-T is described in ClinVar as Benign. ClinVar VariationId is 256709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6 link	c.355+20A>T		intron_variant	Intron 4 of 34	ENST00000298139.7	NP_000544.2	Q14191

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7 link	c.355+20A>T		intron_variant	Intron 4 of 34	1	NM_000553.6	ENSP00000298139.5		Q14191
WRN	ENST00000650667.1 link	n.210-461A>T		intron_variant	Intron 3 of 33			ENSP00000498593.1		A0A494C0M3

Frequencies

GnomAD3 genomes

AF:

0.0447

AC:

6804

AN:

152122

Hom.:

183

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0166

Gnomad AMI

AF:

0.107

Gnomad AMR

AF:

0.0305

Gnomad ASJ

AF:

0.0452

Gnomad EAS

AF:

0.0237

Gnomad SAS

AF:

0.0793

Gnomad FIN

AF:

0.0695

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0596

Gnomad OTH

AF:

0.0431

GnomAD2 exomes

AF:

0.0496

AC:

12456

AN:

251284

AF XY:

0.0519

show subpopulations

Gnomad AFR exome

AF:

0.0149

Gnomad AMR exome

AF:

0.0202

Gnomad ASJ exome

AF:

0.0441

Gnomad EAS exome

AF:

0.0213

Gnomad FIN exome

AF:

0.0682

Gnomad NFE exome

AF:

0.0576

Gnomad OTH exome

AF:

0.0452

GnomAD4 exome

AF:

0.0583

AC:

85146

AN:

1460454

Hom.:

2742

Cov.:

AF XY:

0.0592

AC XY:

42992

AN XY:

726572

show subpopulations

African (AFR)

AF:

0.0141

AC:

472

AN:

33470

American (AMR)

AF:

0.0213

AC:

951

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0444

AC:

1160

AN:

26116

East Asian (EAS)

AF:

0.0231

AC:

916

AN:

39638

South Asian (SAS)

AF:

0.0752

AC:

6480

AN:

86220

European-Finnish (FIN)

AF:

0.0664

AC:

3544

AN:

53400

Middle Eastern (MID)

AF:

0.0554

AC:

319

AN:

5762

European-Non Finnish (NFE)

AF:

0.0613

AC:

68084

AN:

1110786

Other (OTH)

AF:

0.0534

AC:

3220

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

4091

8182

12273

16364

20455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2506

5012

7518

10024

12530

<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:

0.0447

AC:

6806

AN:

152240

Hom.:

184

Cov.:

AF XY:

0.0451

AC XY:

3358

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0166

AC:

691

AN:

41536

American (AMR)

AF:

0.0305

AC:

466

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0452

AC:

157

AN:

3472

East Asian (EAS)

AF:

0.0235

AC:

122

AN:

5188

South Asian (SAS)

AF:

0.0798

AC:

385

AN:

4826

European-Finnish (FIN)

AF:

0.0695

AC:

736

AN:

10594

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0596

AC:

4056

AN:

68018

Other (OTH)

AF:

0.0432

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

344

688

1032

1376

1720

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<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:

0.0508

Hom.:

Bravo

AF:

0.0394

Asia WGS

AF:

0.0550

AC:

191

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Werner syndrome

Benign:3

Dec 05, 2021

Genome-Nilou Lab

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 03, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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_noAF

Benign

-0.83

CADD

Benign

1.4

(source)

DANN

Benign

0.54

PhyloP100

-0.14

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over