8-31141606-C-T

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.3138+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 1,613,698 control chromosomes in the GnomAD database, including 186,689 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 0.41 ( 14117 hom., cov: 30)

Exomes 𝑓: 0.48 ( 172572 hom. )

Consequence

WRN
NM_000553.6 splice_region, intron

Scores

Splicing: ADA: 0.00008950

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.0870

Publications

30 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=-0.79).

BP6

Variant 8-31141606-C-T is Benign according to our data. Variant chr8-31141606-C-T is described in ClinVar as Benign. ClinVar VariationId is 130754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6 link	c.3138+6C>T		splice_region_variant, intron_variant	Intron 25 of 34	ENST00000298139.7	NP_000544.2	Q14191

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
WRN	ENST00000298139.7 link	c.3138+6C>T	splice_region_variant, intron_variant	Intron 25 of 34	1	NM_000553.6	ENSP00000298139.5	Q14191
WRN	ENST00000521620.5 link	n.1771+6C>T	splice_region_variant, intron_variant	Intron 13 of 22	1
WRN	ENST00000650667.1 link	n.*2752+6C>T	splice_region_variant, intron_variant	Intron 24 of 33			ENSP00000498593.1	A0A494C0M3

Frequencies

GnomAD3 genomes

AF:

0.406

AC:

61669

AN:

151764

Hom.:

14117

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.608

Gnomad AMR

AF:

0.393

Gnomad ASJ

AF:

0.499

Gnomad EAS

AF:

0.358

Gnomad SAS

AF:

0.593

Gnomad FIN

AF:

0.572

Gnomad MID

AF:

0.494

Gnomad NFE

AF:

0.492

Gnomad OTH

AF:

0.423

GnomAD2 exomes

AF:

0.470

AC:

118232

AN:

251362

AF XY:

0.483

show subpopulations

Gnomad AFR exome

AF:

0.189

Gnomad AMR exome

AF:

0.404

Gnomad ASJ exome

AF:

0.507

Gnomad EAS exome

AF:

0.338

Gnomad FIN exome

AF:

0.567

Gnomad NFE exome

AF:

0.497

Gnomad OTH exome

AF:

0.491

GnomAD4 exome

AF:

0.481

AC:

703811

AN:

1461818

Hom.:

172572

Cov.:

AF XY:

0.487

AC XY:

353843

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.184

AC:

6163

AN:

33480

American (AMR)

AF:

0.404

AC:

18063

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.509

AC:

13307

AN:

26132

East Asian (EAS)

AF:

0.371

AC:

14730

AN:

39692

South Asian (SAS)

AF:

0.585

AC:

50479

AN:

86258

European-Finnish (FIN)

AF:

0.569

AC:

30405

AN:

53418

Middle Eastern (MID)

AF:

0.558

AC:

3219

AN:

5768

European-Non Finnish (NFE)

AF:

0.485

AC:

538885

AN:

1111958

Other (OTH)

AF:

0.473

AC:

28560

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

22760

45521

68281

91042

113802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15700

31400

47100

62800

78500

<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:

0.406

AC:

61670

AN:

151880

Hom.:

14117

Cov.:

AF XY:

0.412

AC XY:

30594

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.198

AC:

8206

AN:

41440

American (AMR)

AF:

0.392

AC:

5989

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.499

AC:

1729

AN:

3466

East Asian (EAS)

AF:

0.357

AC:

1837

AN:

5142

South Asian (SAS)

AF:

0.595

AC:

2851

AN:

4790

European-Finnish (FIN)

AF:

0.572

AC:

6032

AN:

10546

Middle Eastern (MID)

AF:

0.486

AC:

143

AN:

294

European-Non Finnish (NFE)

AF:

0.492

AC:

33440

AN:

67918

Other (OTH)

AF:

0.423

AC:

892

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1688

3376

5065

6753

8441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

584

1168

1752

2336

2920

<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:

0.466

Hom.:

16036

Bravo

AF:

0.379

Asia WGS

AF:

0.452

AC:

1572

AN:

3478

EpiCase

AF:

0.504

EpiControl

AF:

0.502

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Werner syndrome

Benign:5

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

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 specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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. -

PreventionGenetics, part of Exact Sciences

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

- -

Mar 24, 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

-0.79

CADD

Benign

6.4

(source)

DANN

Benign

0.25

PhyloP100

-0.087

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000090

dbscSNV1_RF

Benign

0.0040

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