rs2737335

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000553.6(WRN):c.3138+7G>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 0.449 in 1,613,658 control chromosomes in the GnomAD database, including 165,330 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 16495 hom., cov: 30)

Exomes 𝑓: 0.45 ( 148835 hom. )

Consequence

WRN
NM_000553.6 splice_region, intron

Scores

Splicing: ADA: 0.00004241

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.618

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 8-31141607-G-A is Benign according to our data. Variant chr8-31141607-G-A is described in ClinVar as [Benign]. Clinvar id is 130755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-31141607-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6 linkuse as main transcript	c.3138+7G>A		splice_region_variant, intron_variant		ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
WRN	ENST00000298139.7 linkuse as main transcript	c.3138+7G>A	splice_region_variant, intron_variant	1	NM_000553.6	P1
WRN	ENST00000521620.5 linkuse as main transcript	n.1771+7G>A	splice_region_variant, intron_variant, non_coding_transcript_variant	1
WRN	ENST00000650667.1 linkuse as main transcript	c.*2752+7G>A	splice_region_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.460

AC:

69854

AN:

151726

Hom.:

16466

Cov.:

show subpopulations

Gnomad AFR

AF:

0.485

Gnomad AMI

AF:

0.282

Gnomad AMR

AF:

0.542

Gnomad ASJ

AF:

0.452

Gnomad EAS

AF:

0.617

Gnomad SAS

AF:

0.321

Gnomad FIN

AF:

0.360

Gnomad MID

AF:

0.459

Gnomad NFE

AF:

0.443

Gnomad OTH

AF:

0.460

GnomAD3 exomes

AF:

0.454

AC:

114078

AN:

251362

Hom.:

26880

AF XY:

0.445

AC XY:

60417

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.487

Gnomad AMR exome

AF:

0.558

Gnomad ASJ exome

AF:

0.447

Gnomad EAS exome

AF:

0.640

Gnomad SAS exome

AF:

0.323

Gnomad FIN exome

AF:

0.364

Gnomad NFE exome

AF:

0.440

Gnomad OTH exome

AF:

0.448

GnomAD4 exome

AF:

0.448

AC:

654666

AN:

1461814

Hom.:

148835

Cov.:

AF XY:

0.443

AC XY:

322115

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.490

Gnomad4 AMR exome

AF:

0.555

Gnomad4 ASJ exome

AF:

0.444

Gnomad4 EAS exome

AF:

0.606

Gnomad4 SAS exome

AF:

0.331

Gnomad4 FIN exome

AF:

0.364

Gnomad4 NFE exome

AF:

0.450

Gnomad4 OTH exome

AF:

0.450

GnomAD4 genome

AF:

0.461

AC:

69937

AN:

151844

Hom.:

16495

Cov.:

AF XY:

0.456

AC XY:

33873

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.486

Gnomad4 AMR

AF:

0.542

Gnomad4 ASJ

AF:

0.452

Gnomad4 EAS

AF:

0.618

Gnomad4 SAS

AF:

0.319

Gnomad4 FIN

AF:

0.360

Gnomad4 NFE

AF:

0.443

Gnomad4 OTH

AF:

0.461

Alfa

AF:

0.448

Hom.:

6519

Bravo

AF:

0.480

Asia WGS

AF:

0.479

AC:

1664

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Werner syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2018

- -

Wiskott-Aldrich syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

Cadd

Benign

0.66

Dann

Benign

0.37

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000042

dbscSNV1_RF

Benign

0.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over