MSRB3

Chr 12AR

methionine sulfoxide reductase B3

Also known as: DFNB74

NCBI Gene: 253827ENSG00000174099UniProt: Q8IXL7

The protein encoded by this gene catalyzes the reduction of methionine sulfoxide to methionine. This enzyme acts as a monomer and requires zinc as a cofactor. Several transcript variants encoding two different isoforms have been found for this gene. One of the isoforms localizes to mitochondria while the other localizes to endoplasmic reticula. [provided by RefSeq, Jul 2010]

Primary Disease Associations & Inheritance

Deafness, autosomal recessive 74MIM #613718
AR
144
ClinVar variants
24
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— MSRB3
🧬
Gene-Disease Validity (ClinGen)
nonsyndromic genetic hearing loss · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
24 Pathogenic / Likely Pathogenic· 58 VUS of 144 total submissions

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.
1.16LOEUF
pLI 0.004
Z-score 1.25
OE 0.55 (0.29–1.16)
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.
0.31Z-score
OE missense 0.92 (0.78–1.08)
100 obs / 109.2 exp
Tolerant

Mild missense constraint

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.0.55 (0.29–1.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.78–1.08)
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.1.04
0≤1.21.6
LoF obs/exp: 5 / 9.1Missense obs/exp: 100 / 109.2Syn Z: -0.21

ClinVar Variant Classifications

144 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic7
VUS58
Likely Benign44
Benign11
Conflicting7
17
Pathogenic
7
Likely Pathogenic
58
VUS
44
Likely Benign
11
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
15
0
17
Likely Pathogenic
3
3
1
0
7
VUS
1
49
7
1
58
Likely Benign
0
1
17
26
44
Benign
0
1
8
2
11
Conflicting
—7
Total5554829144

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

View in ClinVar →

Protein Context — Lollipop Plot

MSRB3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

MSRB3-related deafness

strong
ARUndeterminedAltered Gene Product Structure
Ear
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Deafness, autosomal recessive 74

MIM #613718

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
MSRB3 antioxidant activity is necessary for inner ear cuticular plate structure and hair bundle integrity.
Nayak G et al.·Dis Model Mech
2025
Expanding the Molecular-genetic Spectrum of Canalicular Adenoma-like Subtype of Pleomorphic Adenoma of Salivary Glands.
Klubíčková N et al.·Am J Surg Pathol
2025
Beneath HMGA2 alterations in pleomorphic adenomas: Pathological, immunohistochemical, and molecular insights.
Alsugair Z et al.·Hum Pathol
2024
miR-874-3p Is Identified as a Biomarker for Acute Kidney Injury and Mediates Disease Development via Targeting MSRB3.
Ge J et al.·Nephron
2024
Methionine Sulfoxide Reductase-B3 (MsrB3) Protein Associates with Synaptic Vesicles and its Expression Changes in the Hippocampi of Alzheimer's Disease Patients.
Adams SL et al.·J Alzheimers Dis
2017Cohort
Autosomal recessive non-syndromic hearing loss genes in Pakistan during the previous three decades.
Shadab M et al.·J Cell Mol Med
2024Review
MicroRNA-874-3p Aggravates Doxorubicin-Induced Renal Podocyte Injury via Targeting Methionine Sulfoxide Reductase B3.
Dai Y et al.·Oxid Med Cell Longev
2020
Genome-wide association analysis of hippocampal volume identifies enrichment of neurogenesis-related pathways.
Horgusluoglu-Moloch E et al.·Sci Rep
2019
12q14 microduplication: a new clinical entity reciprocal to the microdeletion syndrome?
Dória S et al.·BMC Med Genomics
2020Case report
Genome-wide association study reveals multiple loci associated with primary tooth development during infancy.
Pillas D et al.·PLoS Genet
2010
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools