4-6301520-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_006005.3(WFS1):c.1725C>T(p.Ala575Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,613,824 control chromosomes in the GnomAD database, including 4,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 419 hom., cov: 34)

Exomes 𝑓: 0.071 ( 4025 hom. )

Consequence

WFS1
NM_006005.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.518

Publications

14 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 4-6301520-C-T is Benign according to our data. Variant chr4-6301520-C-T is described in ClinVar as Benign. ClinVar VariationId is 45438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.518 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3 link	c.1725C>T	p.Ala575Ala	synonymous_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1 link	c.1725C>T	p.Ala575Ala	synonymous_variant	Exon 8 of 8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 link	c.1725C>T	p.Ala575Ala	synonymous_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes

AF:

0.0661

AC:

10068

AN:

152206

Hom.:

420

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0735

Gnomad AMI

AF:

0.181

Gnomad AMR

AF:

0.0514

Gnomad ASJ

AF:

0.102

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.0623

Gnomad FIN

AF:

0.0238

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0734

Gnomad OTH

AF:

0.0626

GnomAD2 exomes

AF:

0.0573

AC:

14395

AN:

251166

AF XY:

0.0585

show subpopulations

Gnomad AFR exome

AF:

0.0739

Gnomad AMR exome

AF:

0.0339

Gnomad ASJ exome

AF:

0.0914

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0283

Gnomad NFE exome

AF:

0.0729

Gnomad OTH exome

AF:

0.0606

GnomAD4 exome

AF:

0.0708

AC:

103422

AN:

1461500

Hom.:

4025

Cov.:

102

AF XY:

0.0705

AC XY:

51292

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.0741

AC:

2480

AN:

33480

American (AMR)

AF:

0.0356

AC:

1591

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0914

AC:

2390

AN:

26136

East Asian (EAS)

AF:

0.000227

AC:

AN:

39698

South Asian (SAS)

AF:

0.0617

AC:

5322

AN:

86256

European-Finnish (FIN)

AF:

0.0295

AC:

1563

AN:

53044

Middle Eastern (MID)

AF:

0.121

AC:

699

AN:

5768

European-Non Finnish (NFE)

AF:

0.0767

AC:

85318

AN:

1112004

Other (OTH)

AF:

0.0671

AC:

4050

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

7155

14311

21466

28622

35777

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3192

6384

9576

12768

15960

<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:

0.0661

AC:

10066

AN:

152324

Hom.:

419

Cov.:

AF XY:

0.0636

AC XY:

4738

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0732

AC:

3042

AN:

41572

American (AMR)

AF:

0.0513

AC:

785

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.102

AC:

355

AN:

3472

East Asian (EAS)

AF:

0.000966

AC:

AN:

5176

South Asian (SAS)

AF:

0.0628

AC:

303

AN:

4826

European-Finnish (FIN)

AF:

0.0238

AC:

253

AN:

10622

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0734

AC:

4990

AN:

68024

Other (OTH)

AF:

0.0619

AC:

131

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

486

972

1457

1943

2429

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<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:

0.0679

Hom.:

584

Bravo

AF:

0.0685

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.0770

EpiControl

AF:

0.0766

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

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

Ala575Ala in Exon 08 of WFS1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 7.3% (274/3738) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2230719).

Nov 20, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 22, 2012

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.

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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.

not provided

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

WFS1-Related Spectrum Disorders

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Autosomal dominant nonsyndromic hearing loss 6

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

3.2

(source)

DANN

Benign

0.84

PhyloP100

-0.52

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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