rs3087409

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000553.6(WRN):c.1577-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0631 in 1,607,294 control chromosomes in the GnomAD database, including 3,545 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.077 ( 509 hom., cov: 32)

Exomes 𝑓: 0.062 ( 3036 hom. )

Consequence

WRN
NM_000553.6 splice_region, intron

Scores

Splicing: ADA: 0.3898

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.54

Publications

17 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 8-31088887-C-A is Benign according to our data. Variant chr8-31088887-C-A is described in ClinVar as [Benign]. Clinvar id is 130753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6 link	c.1577-3C>A		splice_region_variant, intron_variant	Intron 12 of 34	ENST00000298139.7	NP_000544.2	Q14191

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
WRN	ENST00000298139.7 link	c.1577-3C>A	splice_region_variant, intron_variant	Intron 12 of 34	1	NM_000553.6	ENSP00000298139.5	Q14191
WRN	ENST00000521620.5 link	n.278-3C>A	splice_region_variant, intron_variant	Intron 1 of 22	1
WRN	ENST00000650667.1 link	n.*1191-3C>A	splice_region_variant, intron_variant	Intron 11 of 33			ENSP00000498593.1	A0A494C0M3

Frequencies

GnomAD3 genomes

AF:

0.0769

AC:

11674

AN:

151838

Hom.:

508

Cov.:

show subpopulations

Gnomad AFR

AF:

0.128

Gnomad AMI

AF:

0.107

Gnomad AMR

AF:

0.0424

Gnomad ASJ

AF:

0.0453

Gnomad EAS

AF:

0.0239

Gnomad SAS

AF:

0.0795

Gnomad FIN

AF:

0.0697

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0599

Gnomad OTH

AF:

0.0686

GnomAD2 exomes

AF:

0.0566

AC:

13833

AN:

244582

AF XY:

0.0566

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.0252

Gnomad ASJ exome

AF:

0.0435

Gnomad EAS exome

AF:

0.0208

Gnomad FIN exome

AF:

0.0679

Gnomad NFE exome

AF:

0.0561

Gnomad OTH exome

AF:

0.0495

GnomAD4 exome

AF:

0.0616

AC:

89699

AN:

1455338

Hom.:

3036

Cov.:

AF XY:

0.0621

AC XY:

44901

AN XY:

723534

show subpopulations

African (AFR)

AF:

0.129

AC:

4310

AN:

33364

American (AMR)

AF:

0.0275

AC:

1218

AN:

44328

Ashkenazi Jewish (ASJ)

AF:

0.0446

AC:

1157

AN:

25956

East Asian (EAS)

AF:

0.0231

AC:

914

AN:

39556

South Asian (SAS)

AF:

0.0737

AC:

6280

AN:

85262

European-Finnish (FIN)

AF:

0.0662

AC:

3512

AN:

53034

Middle Eastern (MID)

AF:

0.0618

AC:

338

AN:

5466

European-Non Finnish (NFE)

AF:

0.0616

AC:

68316

AN:

1108320

Other (OTH)

AF:

0.0608

AC:

3654

AN:

60052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

3886

7773

11659

15546

19432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0770

AC:

11694

AN:

151956

Hom.:

509

Cov.:

AF XY:

0.0756

AC XY:

5616

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.128

AC:

5322

AN:

41452

American (AMR)

AF:

0.0423

AC:

646

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0453

AC:

157

AN:

3464

East Asian (EAS)

AF:

0.0237

AC:

123

AN:

5184

South Asian (SAS)

AF:

0.0798

AC:

385

AN:

4826

European-Finnish (FIN)

AF:

0.0697

AC:

737

AN:

10572

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0600

AC:

4071

AN:

67884

Other (OTH)

AF:

0.0688

AC:

145

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

555

1111

1666

2222

2777

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0634

Hom.:

1475

Bravo

AF:

0.0765

Asia WGS

AF:

0.0620

AC:

216

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Werner syndrome

Benign:4

Dec 05, 2021

Genome-Nilou Lab

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

- -

Jan 13, 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. -

not specified

Benign:2

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 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. -

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

-0.44

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

1.5

Mutation Taster

=82/18

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.39

dbscSNV1_RF

Benign

0.23

SpliceAI score (max)

0.050

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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rs3087409

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