rs34477820

Positions:

chr8-31058542-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000553.6(WRN):c.95A>G(p.Lys32Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00386 in 1,613,424 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 19 hom. )

Consequence

WRN
NM_000553.6 missense, splice_region

Scores

Splicing: ADA: 0.9915

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8O:1

Conservation

PhyloP100: 5.79

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048146844).

BP6

Variant 8-31058542-A-G is Benign according to our data. Variant chr8-31058542-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135423.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Benign=3, Uncertain_significance=1}. Variant chr8-31058542-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.003 (457/152366) while in subpopulation NFE AF= 0.00541 (368/68036). AF 95% confidence interval is 0.00495. There are 1 homozygotes in gnomad4. There are 183 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6 linkuse as main transcript	c.95A>G	p.Lys32Arg	missense_variant, splice_region_variant	2/35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7 linkuse as main transcript	c.95A>G	p.Lys32Arg	missense_variant, splice_region_variant	2/35	1	NM_000553.6	ENSP00000298139	P1
WRN	ENST00000650667.1 linkuse as main transcript	c.95A>G	p.Lys32Arg	missense_variant, splice_region_variant, NMD_transcript_variant	2/34			ENSP00000498593

Frequencies

GnomAD3 genomes

AF:

0.00300

AC:

457

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00541

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00305

AC:

764

AN:

250438

Hom.:

AF XY:

0.00307

AC XY:

416

AN XY:

135362

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.00148

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000622

Gnomad FIN exome

AF:

0.000787

Gnomad NFE exome

AF:

0.00577

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00395

AC:

5766

AN:

1461058

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

2877

AN XY:

726816

show subpopulations

Gnomad4 AFR exome

AF:

0.000658

Gnomad4 AMR exome

AF:

0.00179

Gnomad4 ASJ exome

AF:

0.000345

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.000859

Gnomad4 FIN exome

AF:

0.00135

Gnomad4 NFE exome

AF:

0.00478

Gnomad4 OTH exome

AF:

0.00310

GnomAD4 genome

AF:

0.00300

AC:

457

AN:

152366

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000793

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00541

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00450

Hom.:

Bravo

AF:

0.00286

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00358

AC:

435

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	WRN: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2019	This variant is associated with the following publications: (PMID: 28063943) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 05, 2020	- -

Werner syndrome

Uncertain:1Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Benign

0.16

Eigen_PC

Benign

0.15

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.69

M_CAP

Benign

0.016

MetaRNN

Benign

0.0048

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

0.99

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.6

REVEL

Benign

0.10

Sift

Uncertain

0.017

Sift4G

Uncertain

0.020

Polyphen

0.70

Vest4

0.21

MVP

0.75

MPC

0.28

ClinPred

0.031

GERP RS

3.7

Varity_R

0.10

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Benign

0.70

SpliceAI score (max)

0.060

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