8-31141764-G-T

Position:

chr8-31141764-G-T

Variant summary

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

The NM_000553.6(WRN):c.3222G>T(p.Leu1074Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,612,852 control chromosomes in the GnomAD database, including 166,265 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 16580 hom., cov: 31)

Exomes 𝑓: 0.45 ( 149685 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 0.235

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:

WRN (HGNC:):

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=6.2455006E-6).

BP6

Variant 8-31141764-G-T is Benign according to our data. Variant chr8-31141764-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 130759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-31141764-G-T 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	Protein	UniProt
WRN	NM_000553.6 linkuse as main transcript	c.3222G>T	p.Leu1074Phe	missense_variant	26/35	ENST00000298139.7	NP_000544.2	Q14191

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
WRN	ENST00000298139.7 linkuse as main transcript	c.3222G>T	p.Leu1074Phe	missense_variant	26/35	1	NM_000553.6	ENSP00000298139.5	Q14191
WRN	ENST00000521620.5 linkuse as main transcript	n.1855G>T		non_coding_transcript_exon_variant	14/23	1
WRN	ENST00000650667.1 linkuse as main transcript	n.*2836G>T		non_coding_transcript_exon_variant	25/34			ENSP00000498593.1	A0A494C0M3
WRN	ENST00000650667.1 linkuse as main transcript	n.*2836G>T		3_prime_UTR_variant	25/34			ENSP00000498593.1	A0A494C0M3

Frequencies

GnomAD3 genomes

AF:

0.462

AC:

70066

AN:

151798

Hom.:

16551

Cov.:

show subpopulations

Gnomad AFR

AF:

0.486

Gnomad AMI

AF:

0.282

Gnomad AMR

AF:

0.543

Gnomad ASJ

AF:

0.454

Gnomad EAS

AF:

0.617

Gnomad SAS

AF:

0.321

Gnomad FIN

AF:

0.360

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.445

Gnomad OTH

AF:

0.463

GnomAD3 exomes

AF:

0.455

AC:

114051

AN:

250884

Hom.:

26905

AF XY:

0.445

AC XY:

60424

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.488

Gnomad AMR exome

AF:

0.559

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:

0.442

Gnomad OTH exome

AF:

0.448

GnomAD4 exome

AF:

0.449

AC:

656181

AN:

1460936

Hom.:

149685

Cov.:

AF XY:

0.444

AC XY:

322859

AN XY:

726824

show subpopulations

Gnomad4 AFR exome

AF:

0.491

Gnomad4 AMR exome

AF:

0.557

Gnomad4 ASJ exome

AF:

0.444

Gnomad4 EAS exome

AF:

0.606

Gnomad4 SAS exome

AF:

0.332

Gnomad4 FIN exome

AF:

0.364

Gnomad4 NFE exome

AF:

0.452

Gnomad4 OTH exome

AF:

0.452

GnomAD4 genome

AF:

0.462

AC:

70148

AN:

151916

Hom.:

16580

Cov.:

AF XY:

0.457

AC XY:

33967

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.486

Gnomad4 AMR

AF:

0.544

Gnomad4 ASJ

AF:

0.454

Gnomad4 EAS

AF:

0.618

Gnomad4 SAS

AF:

0.319

Gnomad4 FIN

AF:

0.360

Gnomad4 NFE

AF:

0.445

Gnomad4 OTH

AF:

0.464

Alfa

AF:

0.446

Hom.:

16421

Bravo

AF:

0.481

TwinsUK

AF:

0.463

AC:

1717

ALSPAC

AF:

0.455

AC:

1754

ESP6500AA

AF:

0.482

AC:

2124

ESP6500EA

AF:

0.459

AC:

3949

ExAC

AF:

0.449

AC:

54519

Asia WGS

AF:

0.480

AC:

1665

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5Other:1

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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

Werner syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
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	Mar 06, 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:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2018	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

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

0.050

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.7

DANN

Benign

0.23

DEOGEN2

Benign

0.049

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.070

MetaRNN

Benign

0.0000062

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.2

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.020

REVEL

Benign

0.023

Sift

Benign

0.76

Sift4G

Benign

0.78

Polyphen

0.0

Vest4

0.0090

MutPred

0.29

Gain of methylation at K1073 (P = 0.0367);

MPC

0.069

ClinPred

0.0033

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.021

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

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