rs1800390

Positions:

chr8-31080997-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000553.6(WRN):c.970A>G(p.Thr324Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,614,046 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 30 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: -1.50

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=0.0030954778).

BP6

Variant 8-31080997-A-G is Benign according to our data. Variant chr8-31080997-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 135449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-31080997-A-G is described in Lovd as [Likely_benign]. Variant chr8-31080997-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00269 (410/152318) while in subpopulation SAS AF= 0.00849 (41/4828). AF 95% confidence interval is 0.00643. There are 2 homozygotes in gnomad4. There are 220 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6 linkuse as main transcript	c.970A>G	p.Thr324Ala	missense_variant	9/35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
WRN	ENST00000298139.7 linkuse as main transcript	c.970A>G	p.Thr324Ala	missense_variant	9/35	1	NM_000553.6	ENSP00000298139	P1
WRN	ENST00000651642.1 linkuse as main transcript	c.265A>G	p.Thr89Ala	missense_variant	3/4			ENSP00000498779
WRN	ENST00000650667.1 linkuse as main transcript	c.*584A>G		3_prime_UTR_variant, NMD_transcript_variant	8/34			ENSP00000498593

Frequencies

GnomAD3 genomes

AF:

0.00269

AC:

410

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00381

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00357

AC:

897

AN:

251292

Hom.:

AF XY:

0.00415

AC XY:

563

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.00905

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00419

Gnomad OTH exome

AF:

0.00523

GnomAD4 exome

AF:

0.00337

AC:

4920

AN:

1461728

Hom.:

Cov.:

AF XY:

0.00354

AC XY:

2571

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.00266

Gnomad4 ASJ exome

AF:

0.00306

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00903

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.00319

Gnomad4 OTH exome

AF:

0.00426

GnomAD4 genome

AF:

0.00269

AC:

410

AN:

152318

Hom.:

Cov.:

AF XY:

0.00295

AC XY:

220

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00849

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00381

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00399

Hom.:

Bravo

AF:

0.00294

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00359

AC:

436

Asia WGS

AF:

0.00347

AC:

AN:

3476

EpiCase

AF:

0.00518

EpiControl

AF:

0.00628

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	WRN: BP4, BS2 -
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	Aug 18, 2020	This variant is associated with the following publications: (PMID: 16786514) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Werner syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 30, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 26, 2014	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Wiskott-Aldrich syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.024

DANN

Benign

0.56

DEOGEN2

Benign

0.10

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.31

M_CAP

Benign

0.0051

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.075

MutationTaster

Benign

1.0

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.85

REVEL

Benign

0.018

Sift

Benign

0.36

Sift4G

Benign

0.43

Polyphen

0.0030

Vest4

0.026

MVP

0.21

MPC

0.064

ClinPred

0.0053

GERP RS

-6.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.022

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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