rs2230009

Positions:

Variant summary

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

The NM_000553.6(WRN):c.340G>A(p.Val114Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0631 in 1,613,308 control chromosomes in the GnomAD database, including 3,572 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V114A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.076 ( 499 hom., cov: 33)

Exomes 𝑓: 0.062 ( 3073 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 0.0360

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 (MetaRNN=0.0013432503).

BP6

Variant 8-31064419-G-A is Benign according to our data. Variant chr8-31064419-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 130760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-31064419-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 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.340G>A	p.Val114Ile	missense_variant	4/35	ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7 linkuse as main transcript	c.340G>A	p.Val114Ile	missense_variant	4/35	1	NM_000553.6	P1
WRN	ENST00000650667.1 linkuse as main transcript	c.210-496G>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0763

AC:

11592

AN:

152008

Hom.:

498

Cov.:

show subpopulations

Gnomad AFR

AF:

0.126

Gnomad AMI

AF:

0.107

Gnomad AMR

AF:

0.0425

Gnomad ASJ

AF:

0.0453

Gnomad EAS

AF:

0.0241

Gnomad SAS

AF:

0.0800

Gnomad FIN

AF:

0.0696

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0602

Gnomad OTH

AF:

0.0690

GnomAD3 exomes

AF:

0.0580

AC:

14588

AN:

251402

Hom.:

554

AF XY:

0.0583

AC XY:

7917

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.0257

Gnomad ASJ exome

AF:

0.0441

Gnomad EAS exome

AF:

0.0216

Gnomad SAS exome

AF:

0.0780

Gnomad FIN exome

AF:

0.0682

Gnomad NFE exome

AF:

0.0580

Gnomad OTH exome

AF:

0.0509

GnomAD4 exome

AF:

0.0618

AC:

90271

AN:

1461182

Hom.:

3073

Cov.:

AF XY:

0.0623

AC XY:

45264

AN XY:

726884

show subpopulations

Gnomad4 AFR exome

AF:

0.127

Gnomad4 AMR exome

AF:

0.0277

Gnomad4 ASJ exome

AF:

0.0447

Gnomad4 EAS exome

AF:

0.0232

Gnomad4 SAS exome

AF:

0.0755

Gnomad4 FIN exome

AF:

0.0664

Gnomad4 NFE exome

AF:

0.0617

Gnomad4 OTH exome

AF:

0.0608

GnomAD4 genome

AF:

0.0763

AC:

11605

AN:

152126

Hom.:

499

Cov.:

AF XY:

0.0749

AC XY:

5570

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.125

Gnomad4 AMR

AF:

0.0424

Gnomad4 ASJ

AF:

0.0453

Gnomad4 EAS

AF:

0.0240

Gnomad4 SAS

AF:

0.0802

Gnomad4 FIN

AF:

0.0696

Gnomad4 NFE

AF:

0.0602

Gnomad4 OTH

AF:

0.0692

Alfa

AF:

0.0582

Hom.:

753

Bravo

AF:

0.0757

TwinsUK

AF:

0.0626

AC:

232

ALSPAC

AF:

0.0664

AC:

256

ESP6500AA

AF:

0.125

AC:

551

ESP6500EA

AF:

0.0564

AC:

485

ExAC

AF:

0.0600

AC:

7282

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 28, 2016	- -
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. -

Werner syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2018

This variant is associated with the following publications: (PMID: 25637295, 27153395, 17764108, 24728327, 23523974) -

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

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.66

CADD

Benign

9.8

DANN

Benign

0.33

DEOGEN2

Benign

0.051

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.14

MetaRNN

Benign

0.0013

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.44

MutationTaster

Benign

1.0

PrimateAI

Benign

0.46

PROVEAN

Benign

0.40

REVEL

Benign

0.096

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.020

MPC

0.055

ClinPred

0.00050

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.025

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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