rs1553879004

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP5

The NM_006005.3(WFS1):c.2389G>A(p.Asp797Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D797V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 34)

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10O:1

Conservation

PhyloP100: 7.50

Publications

6 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 25 uncertain in NM_006005.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-6302185-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2203531.

PP5

Variant 4-6302184-G-A is Pathogenic according to our data. Variant chr4-6302184-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 517360.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3 link	c.2389G>A	p.Asp797Asn	missense_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 link	c.2389G>A	p.Asp797Asn	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.2389G>A	p.Asp797Asn	missense_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Clinical Genetics, Academic Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 10, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25250959, 29447883, 35982127, 33841295, 35810424, 36564540, 37240725, 34387732, 36958120, 36194208) -

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

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 797 of the WFS1 protein (p.Asp797Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 25250959, 29447883). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 517360). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WFS1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Dec 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Wolfram syndrome 1

Pathogenic:1Other: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 rs1553879004 in Wolfram's syndrome yet. -

Jun 15, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PS4,PM5,PM2_SUP,PP3 -

Optic atrophy

Pathogenic:1

Jan 01, 2021

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

WFS1-related disorder

Pathogenic:1

May 30, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The WFS1 c.2389G>A variant is predicted to result in the amino acid substitution p.Asp797Asn. This variant has been reported as causative for autosomal dominant nonsyndromic hearing loss affecting all frequencies (Bai et al. 2014. PubMed ID: 25250959; Cheng et al. 2018. PubMed ID: 29447883). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Rare genetic deafness

Pathogenic:1

May 02, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asp797Asn variant in WFS1 has been reported in a Chinese Han family with a utosomal dominant hearing loss, and segregated with disease in >10 affected rela tives (Bai 2014). Affected family members were evaluated using optic nerve elect roretinogram and fundus imaging, and no abnormalities were reported (Bai 2014). This variant was absent from large population studies. Two different amino acid changes at the same position (p.Asp797Tyr, p.Asp797Val) have also been reported in affected individuals. The p.Asp797Tyr variant has been reported in one indivi dual with sensorineural hearing loss and optic atrophy and segregated in the ind ividual's affected mother (Rendtorff 2011). The p.Asp797Val variant has been rep orted in one individual with autosomal dominant optic atrophy, sensorineural hea ring loss and diabetes mellitus and in one individual with Wolfram syndrome (Roh ayem 2011, Majander 2016). In summary, this variant meets criteria to be classif ied as pathogenic for autosomal dominant hearing loss based on multiple segregat ions with hearing loss reported for a large family with dominant hearing loss (B ai 2014), and absence in controls. -

Autosomal dominant nonsyndromic hearing loss

Pathogenic:1

Nov 08, 2024

Center for Statistical Genetics, Columbia University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

.;D

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

7.5

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.7

N;N

REVEL

Pathogenic

0.81

Sift

Benign

0.093

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.32

B;B

Vest4

0.80

MutPred

0.30

Gain of glycosylation at S792 (P = 0.0053);Gain of glycosylation at S792 (P = 0.0053);

MVP

1.0

ClinPred

0.89

GERP RS

5.6

Varity_R

0.11

gMVP

0.74

Mutation Taster

=22/78

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over