WFS1

Chr 4ADAR

wolframin ER transmembrane glycoprotein

Also known as: CTRCT41, WFRS, WFS, WFSL

NCBI Gene: 7466 ENSG00000109501 UniProt: O76024

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]

Primary Disease Associations & Inheritance

?Cataract 41MIM #116400

{Diabetes mellitus, noninsulin-dependent, association with}MIM #125853

Deafness, autosomal dominant 6/14/38MIM #600965

Wolfram syndrome 1MIM #222300

Wolfram-like syndrome, autosomal dominantMIM #614296

Wolfram syndrome 1MIM #222300

589

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— WFS1

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Gene-Disease Validity (ClinGen)

Wolfram syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

91 Pathogenic / Likely Pathogenic· 371 VUS of 589 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

1.93LOEUF

pLI 0.000

Z-score -3.09

OE 1.62 (1.27–1.93)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-4.71Z-score

OE missense 1.55 (1.47–1.64)

890 obs / 572.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.62 (1.27–1.93)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.55 (1.47–1.64)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.79

0≤1.21.6

LoF obs/exp: 47 / 29.0Missense obs/exp: 890 / 572.6Syn Z: -10.16

ClinVar Variant Classifications

589 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic48

Likely Pathogenic43

VUS371

Likely Benign115

Benign4

Conflicting8

Pathogenic

Likely Pathogenic

371

VUS

115

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	6	33	0	48
Likely Pathogenic	12	19	12	0	43
VUS	1	337	26	7	371
Likely Benign	0	6	24	85	115
Benign	0	0	2	2	4
Conflicting	—				8
Total	22	368	97	94	589

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

WFS1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

WFS1-related Wolfram syndrome (biallelic)

definitive

ARLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure

Dev. DisordersEyeEar

G2P ↗

WFS1-related Wolfram-like syndrome (monoallelic)

definitive

ADUndeterminedAltered Gene Product Structure, Decreased Gene Product Level

Dev. DisordersEyeEar

G2P ↗

frameshift variantmissense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

WOLFRAMIN ER TRANSMEMBRANE GLYCOPROTEIN; WFS1

MIM #606201 · *

?Cataract 41

MIM #116400