4-6301295-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_006005.3(WFS1):c.1500C>T(p.Asn500Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 1,610,910 control chromosomes in the GnomAD database, including 319,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.64 ( 32210 hom., cov: 33)

Exomes 𝑓: 0.62 ( 286987 hom. )

Consequence

WFS1
NM_006005.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.211

Publications

133 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 4-6301295-C-T is Benign according to our data. Variant chr4-6301295-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45437.

BP7

Synonymous conserved (PhyloP=-0.211 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.918 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3 link	c.1500C>T	p.Asn500Asn	synonymous_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 link	c.1500C>T	p.Asn500Asn	synonymous_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.1500C>T	p.Asn500Asn	synonymous_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

AF:

0.644

AC:

97912

AN:

152012

Hom.:

32162

Cov.:

show subpopulations

Gnomad AFR

AF:

0.670

Gnomad AMI

AF:

0.390

Gnomad AMR

AF:

0.701

Gnomad ASJ

AF:

0.682

Gnomad EAS

AF:

0.940

Gnomad SAS

AF:

0.704

Gnomad FIN

AF:

0.567

Gnomad MID

AF:

0.661

Gnomad NFE

AF:

0.602

Gnomad OTH

AF:

0.656

GnomAD2 exomes

AF:

0.665

AC:

165988

AN:

249436

AF XY:

0.662

show subpopulations

Gnomad AFR exome

AF:

0.673

Gnomad AMR exome

AF:

0.751

Gnomad ASJ exome

AF:

0.697

Gnomad EAS exome

AF:

0.940

Gnomad FIN exome

AF:

0.575

Gnomad NFE exome

AF:

0.599

Gnomad OTH exome

AF:

0.655

GnomAD4 exome

AF:

0.623

AC:

909064

AN:

1458780

Hom.:

286987

Cov.:

AF XY:

0.625

AC XY:

453566

AN XY:

725876

show subpopulations

African (AFR)

AF:

0.676

AC:

22620

AN:

33478

American (AMR)

AF:

0.745

AC:

33311

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.696

AC:

18188

AN:

26134

East Asian (EAS)

AF:

0.962

AC:

38192

AN:

39698

South Asian (SAS)

AF:

0.695

AC:

59961

AN:

86258

European-Finnish (FIN)

AF:

0.573

AC:

28860

AN:

50376

Middle Eastern (MID)

AF:

0.628

AC:

3623

AN:

5768

European-Non Finnish (NFE)

AF:

0.598

AC:

665173

AN:

1111978

Other (OTH)

AF:

0.648

AC:

39136

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

25521

51042

76563

102084

127605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18296

36592

54888

73184

91480

<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:

0.644

AC:

98017

AN:

152130

Hom.:

32210

Cov.:

AF XY:

0.646

AC XY:

48027

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.670

AC:

27831

AN:

41512

American (AMR)

AF:

0.701

AC:

10724

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.682

AC:

2367

AN:

3472

East Asian (EAS)

AF:

0.940

AC:

4855

AN:

5164

South Asian (SAS)

AF:

0.703

AC:

3387

AN:

4818

European-Finnish (FIN)

AF:

0.567

AC:

5997

AN:

10578

Middle Eastern (MID)

AF:

0.653

AC:

192

AN:

294

European-Non Finnish (NFE)

AF:

0.602

AC:

40915

AN:

67978

Other (OTH)

AF:

0.660

AC:

1393

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1772

3544

5315

7087

8859

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

792

1584

2376

3168

3960

<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:

0.626

Hom.:

69648

Bravo

AF:

0.656

Asia WGS

AF:

0.818

AC:

2844

AN:

3478

EpiCase

AF:

0.606

EpiControl

AF:

0.612

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:7

Jul 30, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 28, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Type 2 diabetes mellitus

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Potent mutations of WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However, contradictory evidences are found for rs1801214 role in Diabetes mellitus. -

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

-0.60

CADD

Benign

0.31

(source)

DANN

Benign

0.43

PhyloP100

-0.21

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