4-6301521-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_006005.3(WFS1):c.1726G>A(p.Gly576Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00462 in 1,613,806 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G576C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 25 hom., cov: 34)

Exomes 𝑓: 0.0040 ( 188 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications B:12O:1

Conservation

PhyloP100: 5.88

Publications

25 publications found

Variant links:

Genes affected

WFS1 (HGNC:12762): (wolframin ER transmembrane glycoprotein) This gene encodes a transmembrane protein, which is located primarily in the endoplasmic reticulum and ubiquitously expressed with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Mutations in this gene are associated with Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), an autosomal recessive disorder. The disease affects the brain and central nervous system. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]

WFS1 Gene-Disease associations (from GenCC):

Wolfram-like syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
Wolfram syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
autosomal dominant nonsyndromic hearing loss 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
cataract 41
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Wolfram syndrome 1
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
type 2 diabetes mellitus
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

WFS1 links:

ENSG00000286176 (HGNC:58722):

ENSG00000286176 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005336702).

BP6

Variant 4-6301521-G-A is Benign according to our data. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439. Variant chr4-6301521-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45439.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3 link	c.1726G>A	p.Gly576Ser	missense_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 link	c.1726G>A	p.Gly576Ser	missense_variant	Exon 8 of 8		NP_001139325.1	O76024A0A0S2Z4V6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 link	c.1726G>A	p.Gly576Ser	missense_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

AF:

0.0110

AC:

1672

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0712

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00954

AC:

2397

AN:

251166

AF XY:

0.00806

show subpopulations

Gnomad AFR exome

AF:

0.0242

Gnomad AMR exome

AF:

0.0191

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.0670

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00396

AC:

5789

AN:

1461478

Hom.:

188

Cov.:

AF XY:

0.00374

AC XY:

2721

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.0235

AC:

788

AN:

33480

American (AMR)

AF:

0.0185

AC:

827

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26136

East Asian (EAS)

AF:

0.0877

AC:

3482

AN:

39700

South Asian (SAS)

AF:

0.00195

AC:

168

AN:

86254

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

53030

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000224

AC:

249

AN:

1111994

Other (OTH)

AF:

0.00431

AC:

260

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

446

893

1339

1786

2232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0110

AC:

1674

AN:

152328

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

837

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0244

AC:

1014

AN:

41572

American (AMR)

AF:

0.0148

AC:

227

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0712

AC:

368

AN:

5172

South Asian (SAS)

AF:

0.00248

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68028

Other (OTH)

AF:

0.0109

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

179

268

358

447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00313

Hom.:

Bravo

AF:

0.0135

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0186

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00892

AC:

1083

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Benign:12Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Jul 23, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 04, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 06, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gly576Ser in Exon 08 of WFS1: This variant is not expected to have clinical sign ificance because it has been identified in 1.9% (72/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs1805069). -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

WFS1-Related Spectrum Disorders

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Monogenic diabetes

Benign:1

Feb 08, 2019

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG criteria: BA1 (6.7% in gnomAD SA, 2.3% in gnomAD African), BS2 (62 homozygotes in gnomAD)=Benign (REVEL 0.534 + precictor evidence not consistent, not using) -

Autosomal dominant nonsyndromic hearing loss 6

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Wolfram syndrome 1

Other:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain risk allele

Review Status:criteria provided, single submitter

Collection Method:research

Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy.However no sufficient evidence is found to ascertain the role of this particular variant rs1805069 yet. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.67

.;T

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

5.9

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.54

Sift

Benign

0.031

D;D

Sift4G

Uncertain

0.022

D;D

Polyphen

0.88

P;P

Vest4

0.65

MVP

0.99

ClinPred

0.027

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.76

Mutation Taster

=88/12

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over