WFS1

wolframin ER transmembrane glycoprotein

Basic information

Region (hg38): 4:6269849-6303265

Previous symbols: [ "DFNA6", "DFNA14", "DFNA38" ]

Links

ENSG00000109501 ∙ NCBI:7466 ∙ OMIM:606201 ∙ HGNC:12762 ∙ Uniprot:O76024 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Wolfram syndrome 1 (Strong), mode of inheritance: AR
• Wolfram-like syndrome (Strong), mode of inheritance: AD
• Wolfram syndrome 1 (Definitive), mode of inheritance: AR
• Wolfram-like syndrome (Definitive), mode of inheritance: AD
• Wolfram-like syndrome (Strong), mode of inheritance: AD
• Wolfram syndrome 1 (Strong), mode of inheritance: AR
• Wolfram syndrome (Supportive), mode of inheritance: AR
• autosomal dominant nonsyndromic hearing loss (Supportive), mode of inheritance: AD
• early-onset nuclear cataract (Supportive), mode of inheritance: AD
• Wolfram-like syndrome (Supportive), mode of inheritance: AD
• Wolfram-like syndrome (Definitive), mode of inheritance: AD
• cataract 41 (Limited), mode of inheritance: AD
• cataract 41 (Strong), mode of inheritance: AD
• autosomal dominant nonsyndromic hearing loss 6 (Strong), mode of inheritance: AD
• type 2 diabetes mellitus (Limited), mode of inheritance: Unknown
• Wolfram syndrome 1 (Strong), mode of inheritance: AR
• Wolfram-like syndrome (Strong), mode of inheritance: AD
• Wolfram-like syndrome (Definitive), mode of inheritance: AD
• Wolfram syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Wolfram syndrome 1	AR	Audiologic/Otolaryngologic; Endocrine; Renal	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Recognition and interventions related to endocrine anomalies (eg, diabetes insipidus, diabetes mellitus) may be beneficial; Awareness of the possibility of renal anomalies (eg, hydronephrosis) may allow surveillance and management to potentially benefit renal/urologic function	Audiologic/Otolaryngologic; Endocrine; Neurologic; Ophthalmologic; Renal	5956444; 8595423; 9817917; 10521293; 11709537; 11317350; 11709538; 12107816; 12181639; 15070927; 16151413; 17568405; 17492394; 18806274; 21823543; 21917145; 21446023; 22238590; 21968327; 22498363; 22226368; 23531866
A small proportion of individuals may have congenital deafness

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the WFS1 gene.

• not provided (67 variants)
• Wolfram syndrome 1 (22 variants)
• WFS1-related disorder (4 variants)
• Diabetes mellitus (3 variants)
• WFS1-Related Spectrum Disorders (3 variants)
• Rare genetic deafness (3 variants)
• Cataract 41;Wolfram syndrome 1;Autosomal dominant nonsyndromic hearing loss 6;Wolfram-like syndrome;Type 2 diabetes mellitus (2 variants)
• Inborn genetic diseases (2 variants)
• Wolfram syndrome (2 variants)
• Wolfram-like syndrome (2 variants)
• Wolfram syndrome 1;Wolfram-like syndrome;Cataract 41;Autosomal dominant nonsyndromic hearing loss 6;Type 2 diabetes mellitus (2 variants)
• Cataract 41;Wolfram syndrome 1;Wolfram-like syndrome;Autosomal dominant nonsyndromic hearing loss 6;Type 2 diabetes mellitus (1 variants)
• Cataract 41 (1 variants)
• Cataract 41;Autosomal dominant nonsyndromic hearing loss 6;Type 2 diabetes mellitus;Wolfram syndrome 1;Wolfram-like syndrome (1 variants)
• Type 2 diabetes mellitus (1 variants)
• See cases (1 variants)
• Type 2 diabetes mellitus;Cataract 41;Autosomal dominant nonsyndromic hearing loss 6;Wolfram syndrome 1;Wolfram-like syndrome (1 variants)
• Wolfram syndrome 1;Rare genetic deafness (1 variants)
• Wolfram syndrome 1;Cataract 41;Autosomal dominant nonsyndromic hearing loss 6;Type 2 diabetes mellitus;Wolfram-like syndrome (1 variants)
• Autosomal dominant nonsyndromic hearing loss 6 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the WFS1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			11	358	24	393
missense	20	42	615	36	1	714
nonsense	29	18	1			48
start loss						0
frameshift	27	14	1			42
inframe indel	6	9	23	1		39
splice donor/acceptor (+/-2bp)	4	3				7
splice region			8	15		23
non coding			12	69	80	161
Total	86	86	663	464	105

Highest pathogenic variant AF is 0.0000854

Variants in WFS1

This is a list of pathogenic ClinVar variants found in the WFS1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-6269872-G-T		WFS1-Related Spectrum Disorders • Autosomal dominant nonsyndromic hearing loss 6 • Wolfram syndrome 1	Conflicting classifications of pathogenicity (Jan 13, 2018)
4-6269879-A-G		Autosomal dominant nonsyndromic hearing loss 6 • WFS1-Related Spectrum Disorders • Wolfram syndrome 1	Conflicting classifications of pathogenicity (Jan 01, 2023)
4-6269887-G-T		WFS1-Related Spectrum Disorders • Autosomal dominant nonsyndromic hearing loss 6 • Wolfram syndrome 1	Conflicting classifications of pathogenicity (Jan 12, 2018)
4-6269890-C-T		Autosomal dominant nonsyndromic hearing loss 6 • WFS1-Related Spectrum Disorders • Wolfram syndrome 1	Conflicting classifications of pathogenicity (May 01, 2022)
4-6269891-A-G		Autosomal dominant nonsyndromic hearing loss 6 • WFS1-Related Spectrum Disorders • Wolfram syndrome 1	Conflicting classifications of pathogenicity (Jan 13, 2018)
4-6269893-A-G		WFS1-Related Spectrum Disorders • Autosomal dominant nonsyndromic hearing loss 6 • Wolfram syndrome 1	Conflicting classifications of pathogenicity (Jan 13, 2018)
4-6269914-A-G		WFS1-Related Spectrum Disorders • Autosomal dominant nonsyndromic hearing loss 6 • Wolfram syndrome 1	Conflicting classifications of pathogenicity (Jan 13, 2018)
4-6269915-T-G		WFS1-Related Spectrum Disorders • Autosomal dominant nonsyndromic hearing loss 6 • Wolfram syndrome 1	Conflicting classifications of pathogenicity (Jan 13, 2018)
4-6269920-C-G		Autosomal dominant nonsyndromic hearing loss 6 • WFS1-Related Spectrum Disorders	Uncertain significance (Jan 12, 2018)
4-6269920-C-T		Wolfram syndrome 1	Benign (-)
4-6269927-G-C		Autosomal dominant nonsyndromic hearing loss 6 • WFS1-Related Spectrum Disorders • Wolfram syndrome 1	Conflicting classifications of pathogenicity (Jan 13, 2018)
4-6269965-C-G		WFS1-Related Spectrum Disorders • Autosomal dominant nonsyndromic hearing loss 6	Uncertain significance (Jan 12, 2018)
4-6269965-C-T		Wolfram syndrome 1	Benign (-)
4-6269977-G-C		WFS1-Related Spectrum Disorders • Autosomal dominant nonsyndromic hearing loss 6 • Wolfram syndrome 1	Conflicting classifications of pathogenicity (Aug 04, 2022)
4-6269993-C-T		not specified • Wolfram syndrome 1	Likely benign (Dec 09, 2016)
4-6270025-C-T		not specified • WFS1-Related Spectrum Disorders • Autosomal dominant nonsyndromic hearing loss 6 • Wolfram syndrome 1	Benign/Likely benign (Jan 13, 2018)
4-6270028-C-A			Benign (Jun 09, 2015)
4-6270040-G-GGCGCGGTGGCTGTGGGCA			Benign (Jul 15, 2018)
4-6270099-T-C			Benign (Jun 23, 2018)
4-6270243-G-C			Benign (Jul 11, 2018)
4-6271838-G-C			Uncertain significance (Apr 21, 2022)
4-6276042-G-T			Uncertain significance (Apr 21, 2022)
4-6277196-G-C			Benign (Jun 29, 2018)
4-6277246-G-C			Benign (Jun 29, 2018)
4-6277317-T-C			Likely benign (Dec 24, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
WFS1	protein_coding	protein_coding	ENST00000226760	7	33417

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.62e-38	2.56e-9	125632	0	116	125748	0.000461

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-4.71	890	573	1.55	0.0000410	5744
Missense in Polyphen		302	217.58	1.388		2233
Synonymous	-10.2	476	265	1.79	0.0000216	1822
Loss of Function	-3.09	47	29.0	1.62	0.00000136	321

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000817	0.000817
Ashkenazi Jewish	0.00	0.00
East Asian	0.00103	0.00103
Finnish	0.000328	0.000323
European (Non-Finnish)	0.000509	0.000492
Middle Eastern	0.00103	0.00103
South Asian	0.000296	0.000294
Other	0.000327	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store. {ECO:0000269|PubMed:16989814}.
• Disease: DISEASE: Wolfram syndrome 1 (WFS1) [MIM:222300]: A rare disorder characterized by juvenile-onset insulin-dependent diabetes mellitus with optic atrophy. Other manifestations include diabetes insipidus, sensorineural deafness, dementia, psychiatric illnesses. {ECO:0000269|PubMed:10521293, ECO:0000269|PubMed:11161832, ECO:0000269|PubMed:11295831, ECO:0000269|PubMed:15605410, ECO:0000269|PubMed:21538838, ECO:0000269|PubMed:22226368, ECO:0000269|PubMed:9771706, ECO:0000269|PubMed:9817917}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal dominant, 6 (DFNA6) [MIM:600965]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA6 is a low-frequency hearing loss in which frequencies of 2000 Hz and below are predominantly affected. Many patients have tinnitus, but there are otherwise no associated features such as vertigo. Because high-frequency hearing is generally preserved, patients retain excellent understanding of speech, although presbycusis or noise exposure may cause high-frequency loss later in life. DFNA6 worsens over time without progressing to profound deafness. {ECO:0000269|PubMed:11709537, ECO:0000269|PubMed:11709538, ECO:0000269|PubMed:12181639, ECO:0000269|PubMed:17517145, ECO:0000269|PubMed:18518985, ECO:0000269|PubMed:18688868, ECO:0000269|PubMed:21356526, ECO:0000269|PubMed:24462758, ECO:0000269|PubMed:25388789}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Wolfram-like syndrome autosomal dominant (WFSL) [MIM:614296]: A disease characterized by the clinical triad of congenital progressive hearing impairment, diabetes mellitus, and optic atrophy. The hearing impairment, which is usually diagnosed in the first decade of life, is relatively constant and alters mainly low- and middle-frequency ranges. {ECO:0000269|PubMed:16648378, ECO:0000269|PubMed:20069065, ECO:0000269|PubMed:21538838}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cataract 41 (CTRCT41) [MIM:116400]: An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. {ECO:0000269|PubMed:23531866}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Protein processing in endoplasmic reticulum - Homo sapiens (human);XBP1(S) activates chaperone genes;Post-translational protein phosphorylation;Post-translational protein modification;Metabolism of proteins;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (Consensus)

Recessive Scores

• pRec: 0.110

Intolerance Scores

• loftool: 0.00682
• rvis_EVS: -0.1
• rvis_percentile_EVS: 45.69

Haploinsufficiency Scores

• pHI: 0.146
• ghis: 0.493

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.881

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Wfs1
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); digestive/alimentary phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: wfs1b
• Affected structure: pancreatic B cell
• Phenotype tag: abnormal
• Phenotype quality: decreased area

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;kidney development;renal water homeostasis;ER overload response;visual perception;sensory perception of sound;protein maturation by protein folding;ubiquitin-dependent ERAD pathway;pancreas development;positive regulation of protein ubiquitination;endoplasmic reticulum calcium ion homeostasis;response to endoplasmic reticulum stress;IRE1-mediated unfolded protein response;olfactory behavior;glucose homeostasis;negative regulation of programmed cell death;negative regulation of DNA-binding transcription factor activity;negative regulation of neuron apoptotic process;post-translational protein modification;cellular protein metabolic process;positive regulation of growth;protein stabilization;nervous system process;positive regulation of protein metabolic process;positive regulation of calcium ion transport;calcium ion homeostasis;negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway;negative regulation of ATF6-mediated unfolded protein response;negative regulation of type B pancreatic cell apoptotic process
• Cellular component: proteasome complex;endoplasmic reticulum;endoplasmic reticulum lumen;endoplasmic reticulum membrane;integral component of endoplasmic reticulum membrane;integral component of synaptic vesicle membrane;dendrite
• Molecular function: protein binding;calmodulin binding;ubiquitin protein ligase binding;activating transcription factor binding;calcium-dependent protein binding;ATPase binding