MSRB3

Summary

MSRB3 (methionine sulfoxide reductase B3, HGNC:27375) is a protein-coding gene on chromosome 12q14.3, encoding Methionine-R-sulfoxide reductase B3 (Q8IXL7). Catalyzes the reduction of free and protein-bound methionine sulfoxide to methionine.

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.

Source: NCBI Gene 253827 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 38
• Clinical variants (ClinVar): 129 total — 4 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001031679

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27375
Approved symbol	MSRB3
Name	methionine sulfoxide reductase B3
Location	12q14.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ36866, DKFZp686C1178
Ensembl gene	ENSG00000174099
Ensembl biotype	protein_coding
OMIM	613719
Entrez	253827

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 22 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000308259, ENST00000355192, ENST00000446731, ENST00000535143, ENST00000535239, ENST00000535664, ENST00000538045, ENST00000538725, ENST00000540804, ENST00000541189, ENST00000541897, ENST00000614640, ENST00000642404, ENST00000642411, ENST00000645872, ENST00000646299, ENST00000647481, ENST00000909995, ENST00000909996, ENST00000945002, ENST00000945003, ENST00000945004, ENST00000945005, ENST00000945006, ENST00000945007, ENST00000945008

RefSeq mRNA: 4 — MANE Select: NM_001031679 NM_001031679, NM_001193460, NM_001193461, NM_198080

CCDS: CCDS31853, CCDS8973

Canonical transcript exons

ENST00000308259 — 7 exons

Exon	Start	End
ENSE00001243871	65326826	65326934
ENSE00001371716	65328526	65328603
ENSE00003563053	65453728	65453825
ENSE00003600962	65368998	65369026
ENSE00003641223	65278683	65278865
ENSE00003692858	65308529	65308655
ENSE00003902807	65463155	65466907

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 99.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.8922 / max 297.9287, expressed in 1349 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126488	12.5942	1319
126490	0.8440	213
126487	0.6646	343
126489	0.4548	239
126493	0.1667	54
126492	0.1508	48
126491	0.0172	6

Top tissues by expression

262 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
saphenous vein	UBERON:0007318	99.37	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.12	gold quality
urethra	UBERON:0000057	98.79	gold quality
seminal vesicle	UBERON:0000998	98.74	gold quality
visceral pleura	UBERON:0002401	98.70	gold quality
left ventricle myocardium	UBERON:0006566	98.49	gold quality
popliteal artery	UBERON:0002250	98.46	gold quality
tibial artery	UBERON:0007610	98.46	gold quality
right coronary artery	UBERON:0001625	98.41	gold quality
parietal pleura	UBERON:0002400	98.40	gold quality
smooth muscle tissue	UBERON:0001135	98.39	gold quality
aorta	UBERON:0000947	98.21	gold quality
myocardium	UBERON:0002349	98.18	gold quality
vena cava	UBERON:0004087	98.14	gold quality
vastus lateralis	UBERON:0001379	98.08	gold quality
cauda epididymis	UBERON:0004360	97.91	gold quality
descending thoracic aorta	UBERON:0002345	97.87	gold quality
thoracic aorta	UBERON:0001515	97.86	gold quality
ascending aorta	UBERON:0001496	97.83	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.80	gold quality
quadriceps femoris	UBERON:0001377	97.73	gold quality
superficial temporal artery	UBERON:0001614	97.63	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.55	gold quality
coronary artery	UBERON:0001621	97.52	gold quality
biceps brachii	UBERON:0001507	97.50	gold quality
lower esophagus	UBERON:0013473	97.49	gold quality
left coronary artery	UBERON:0001626	97.45	gold quality
tibia	UBERON:0000979	97.43	gold quality
myometrium	UBERON:0001296	97.13	gold quality
deltoid	UBERON:0001476	97.00	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	29.86
E-HCAD-6	yes	28.36
E-MTAB-8410	yes	20.55
E-CURD-119	yes	13.56
E-ANND-3	yes	9.01
E-GEOD-130148	yes	4.01
E-GEOD-110499	no	405.75

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

180 targeting MSRB3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-302C-5P	99.97	72.56	3642

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 15)

• an in vitro assay revealed that p.Cys89Gly completely abolished MSRB3 enzymatic activity and that p.Arg19X is a null allele for MSRB3 mitochondrial isoforms, indicating that DFNB74 deafness might be a mitochondrial disease limited to the inner ear. (PMID:21185009)
• Results identified an antimicrobial peptide from the human methionine sulfoxide reductase B3 protein. (PMID:22027001)
• Taken together, these data provide evidence that the ER type of MsrB, MsrB3A, plays an important role in protection mechanisms against oxidative, cold and heat stresses and, moreover, in the regulation of fruit fly aging. (PMID:22310715)
• these data provide evidence that the ER-type of MsrB3 plays an important role in protection against ER stress, suggesting that MsrB3 may be involved in the regulation of ER homeostasis. (PMID:22405767)
• DNA methylation shows genome-wide association of NFIX, RAPGEF2 and MSRB3 with gestational age at birth. (PMID:22422452)
• MsrB3 deficiency activates the cell cycle inhibitors p21 and p27. (PMID:24583268)
• The data suggest that MsrB3 attenuates HO-1 induction by inhibiting reactive oxygen species production, endoplasmic reticulum stress, and Nrf2 activation. (PMID:27059143)
• MsrB3 plays an important role in cancer cell survival through the modulation of the intrinsic apoptosis pathway. (PMID:28007593)
• Taken together, our results suggest that MsrB3 plays a critical role in cancer cell apoptosis through the modulation of ER stress status. (PMID:28389299)
• Oncogene induction in differentiated cells induces massive DNA damage, mammary stem cells are resistant, owing to a preemptive program driven by ZEB1 and MSRB3. The prevention of oncogene-induced DNA damage precludes induction of the oncosuppressive p53-dependent DNA-damage response, thereby increasing stem cells’ intrinsic susceptibility to malignant transformation. (PMID:28394329)
• This characterization of GWAS-implicated MSRB3 protein expression in human hippocampus suggests that patterns of neuronal and vascular MsrB3 protein expression reflect or underlie pathology associated with Alzheimer disease. (PMID:28777754)
• we characterise the mammalian enzyme Msr B3. There are two splice variants of this enzyme that differ only in their N-terminal signal sequence, which directs the protein to either the endoplasmic reticulum (ER) or mitochondria (PMID:29420254)
• individuals with MSRB3 rs61921502 minor allele had increased odds for brain infarcts on MRI compared to those with no minor allele (PMID:30775993)
• MSRB3 promotes the progression of clear cell renal cell carcinoma via regulating endoplasmic reticulum stress. (PMID:31889586)
• MicroRNA-874-3p Aggravates Doxorubicin-Induced Renal Podocyte Injury via Targeting Methionine Sulfoxide Reductase B3. (PMID:32908641)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	msrb3	ENSDARG00000045658
mus_musculus	Msrb3	ENSMUSG00000051236
rattus_norvegicus	Msrb3	ENSRNOG00000042668
drosophila_melanogaster	SelR	FBGN0267376
caenorhabditis_elegans		WBGENE00018419

Paralogs (3): MSRB2 (ENSG00000148450), MSRA (ENSG00000175806), MSRB1 (ENSG00000198736)

Protein

Protein identifiers

Methionine-R-sulfoxide reductase B3 — Q8IXL7 (reviewed: Q8IXL7)

All UniProt accessions (8): Q8IXL7, A0A2R8Y7J8, F5H199, F5H4C9, F5H6G9, F5H7C4, H0YFW5, H7C2B7

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the reduction of free and protein-bound methionine sulfoxide to methionine. Isoform 2 is essential for hearing.

Subunit / interactions. Monomer.

Subcellular location. Endoplasmic reticulum Mitochondrion.

Tissue specificity. Widely expressed.

Disease relevance. Deafness, autosomal recessive, 74 (DFNB74) [MIM:613718] A form of non-syndromic sensorineural deafness characterized by prelingual, bilateral, profound 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. The disease is caused by variants affecting the gene represented in this entry. A nonsense mutation affecting exclusively mitochondrial isoform 2 is sufficient to produce hearing loss.

Cofactor. Binds 1 zinc ion per subunit.

Miscellaneous. Has a transit peptide.

Similarity. Belongs to the MsrB Met sulfoxide reductase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IXL7-1	1, A	yes
Q8IXL7-2	2, B, C, D

RefSeq proteins (4): NP_001026849, NP_001180389, NP_001180390, NP_932346 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002579	Met_Sox_Rdtase_MsrB_dom	Domain
IPR011057	Mss4-like_sf	Homologous_superfamily
IPR028427	Met_Sox_Rdtase_MsrB	Family

Pfam: PF01641

Enzyme classification (BRENDA):

• EC 1.8.4.12 — peptide-methionine (R)-S-oxide reductase (BRENDA: 101 organisms, 214 substrates, 7 inhibitors, 64 Km, 65 kcat entries)
• EC 1.8.4.B3 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Substrate kinetics (BRENDA)

19 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
THIOREDOXIN	0.004–7	9
L-METHIONINE-(R)-S-OXIDE	0.054–1.3	8
DABSYL-L-METHIONINE (R)-S-OXIDE	0.03–0.085	7
DABSYL-L-METHIONINE (R)-SULFOXIDE	0.02–0.06	6
N-ACETYL-L-METHIONINE-(R)-S-OXIDE	0.043–0.429	6
DITHIOTHREITOL	0.0091–2	4
L-METHIONINE (R)-SULFOXIDE	1.451–67	3
TRYPAREDOXIN I	0.0016–0.0021	3
ACETYL-L-METHIONINE (R)-SULFOXIDE N-METHYL ESTER	0.14–2.2	2
N-ACETYL-L-METHIONINE (R)-SULFOXIDE	0.049	2
(S)-1-NONEN-4-OL	1.2	1
CDSP32	0.0002	1
GLUTAREDOXIN	0.0028	1
GLUTAREDOXIN C4	0.0068	1
GLUTAREDOXIN S12	0.0005	1

Catalyzed reactions (Rhea), 2 shown:

• [thioredoxin]-disulfide + L-methionine + H2O = L-methionine (R)-S-oxide + [thioredoxin]-dithiol (RHEA:21260)
• L-methionyl-[protein] + [thioredoxin]-disulfide + H2O = L-methionyl-(R)-S-oxide-[protein] + [thioredoxin]-dithiol (RHEA:24164)

UniProt features (36 total): strand 8, turn 5, helix 5, binding site 4, mutagenesis site 3, modified residue 2, signal peptide 1, chain 1, splice variant 1, sequence variant 1, sequence conflict 1, domain 1, region of interest 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6QA0	X-RAY DIFFRACTION	1.71
6Q9V	X-RAY DIFFRACTION	1.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IXL7-F1	86.73	0.73

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 158 (nucleophile)

Ligand- & substrate-binding residues (4): 86; 89; 135; 138

Post-translational modifications (2): 42, 183

Mutagenesis-validated functional residues (3):

Position	Phenotype
141	30-fold reduction in activity.
160	7000-fold reduction in activity.
160	500-fold reduction in activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5676934	Protein repair
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 156 (showing top): BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, NKX62_Q2, TGACATY_UNKNOWN, TGGNNNNNNKCCAR_UNKNOWN, JAATINEN_HEMATOPOIETIC_STEM_CELL_UP, AML1_01, CUI_TCF21_TARGETS_2_DN, CART1_01, TAATTA_CHX10_01, ZHAN_MULTIPLE_MYELOMA_CD2_DN, GEORGES_TARGETS_OF_MIR192_AND_MIR215, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_A_SULFUR_GROUP_OF_DONORS_DISULFIDE_AS_ACCEPTOR, LIU_PROSTATE_CANCER_DN, CHICAS_RB1_TARGETS_CONFLUENT

GO Biological Process (2): response to oxidative stress (GO:0006979), protein repair (GO:0030091)

GO Molecular Function (7): zinc ion binding (GO:0008270), peptide-methionine (R)-S-oxide reductase activity (GO:0033743), L-methionine (R)-S-oxide reductase activity (GO:0033745), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on a sulfur group of donors, disulfide as acceptor (GO:0016671), metal ion binding (GO:0046872)

GO Cellular Component (4): cytoplasm (GO:0005737), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
oxidoreductase activity, acting on a sulfur group of donors, disulfide as acceptor	2
cellular anatomical structure	2
intracellular membrane-bounded organelle	2
response to stress	1
protein metabolic process	1
transition metal ion binding	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
oxidoreductase activity, acting on a sulfur group of donors	1
cation binding	1
intracellular anatomical structure	1
endomembrane system	1

Protein interactions and networks

STRING

1776 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MSRB3	MSRA	Q9UJ68	742
MSRB3	LEMD3	Q9Y2U8	593
MSRB3	LLPH	Q9BRT6	564
MSRB3	LHFPL5	Q8TAF8	563
MSRB3	F5H6H0	F5H6H0	517
MSRB3	GRXCR1	A8MXD5	490
MSRB3	PJVK	Q0ZLH3	489
MSRB3	TPRN	Q4KMQ1	486
MSRB3	RXFP2	Q8WXD0	468
MSRB3	ACSS3	Q9H6R3	462
MSRB3	XBP1	P17861	451
MSRB3	TMIE	Q8NEW7	446
MSRB3	E9PNW1	E9PNW1	440
MSRB3	RFX8	Q6ZV50	438
MSRB3	ACAD9	Q9H845	434

IntAct

18 interactions, top by confidence:

A	B	Type	Score
MSRB3	TCF4	psi-mi:“MI:0915”(physical association)	0.560
GOLGA2	MSRB3	psi-mi:“MI:0915”(physical association)	0.560
MSRB3	TRIP6	psi-mi:“MI:0915”(physical association)	0.560
PRDM4	MSRB3	psi-mi:“MI:0915”(physical association)	0.560
MSRB3	GOLGA2	psi-mi:“MI:0915”(physical association)	0.560
MSRB3	PRDM4	psi-mi:“MI:0915”(physical association)	0.560
TCF4	MSRB3	psi-mi:“MI:0915”(physical association)	0.560
TRIP6	MSRB3	psi-mi:“MI:0915”(physical association)	0.560
FTH1	A2ML1	psi-mi:“MI:0914”(association)	0.530
MSRB3	LNX2	psi-mi:“MI:0915”(physical association)	0.370
MSRB3	SPOP	psi-mi:“MI:0914”(association)	0.350
DCUN1D4	ARL4C	psi-mi:“MI:0914”(association)	0.350
MSRB3	CTBP2	psi-mi:“MI:0914”(association)	0.350

BioGRID (99): MSRB3 (Two-hybrid), MSRB3 (Two-hybrid), MSRB3 (Two-hybrid), MSRB3 (Two-hybrid), MSRB3 (Affinity Capture-RNA), MSRB3 (Affinity Capture-RNA), MSRB3 (Affinity Capture-MS), MSRB3 (Co-fractionation), MSRB3 (Two-hybrid), MSRB3 (Two-hybrid), KLHL7 (Affinity Capture-MS), RBP4 (Affinity Capture-MS), SPOP (Affinity Capture-MS), MSRB3 (Affinity Capture-MS), C1QL1 (Affinity Capture-MS)

ESM2 similar proteins: B4GUZ2, O49707, O64903, O76454, O81263, P00257, P10109, P10606, P24483, P25566, P46656, P54150, P54151, Q01H90, Q05B87, Q08C57, Q0DC89, Q16595, Q1JPN0, Q2GNZ6, Q2HVD6, Q4FZX5, Q4P4Y2, Q5BFH3, Q5NTH3, Q5R930, Q5REG2, Q69SV0, Q6AUK5, Q6EU10, Q6NW52, Q6Z690, Q6ZQ88, Q78J03, Q7XUR2, Q84JT6, Q8BU85, Q8GWF4, Q8INK9, Q8IXL7

Diamond homologs: A0K833, A1V4U8, A1VNB7, A2SBI6, A2SGN7, A3M4Q3, A4G5V5, A4JEZ1, A4XVB1, A6T7R0, A6V3R3, A7ZMP8, A8A0X0, A9AJS6, A9MFH4, A9N292, B0BYW4, B0VC45, B0VR86, B1IPF3, B1J4W5, B1JTT6, B1LDV3, B1XGN8, B1YRN6, B2HYT2, B4EBK9, B4T3Y1, B4TGC8, B4TUA8, B5F860, B5FJF9, B5XS71, B5YQ71, B6IBJ9, B7H3X2, B7I415, B7L6Q3, B7LQ21, B7M1J2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

129 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	7
Uncertain significance	55
Likely benign	39
Benign	11

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
2427638	NC_000012.11:g.(?65720586)(65722403_?)del	Pathogenic
31055	NM_001031679.3(MSRB3):c.244T>G (p.Cys82Gly)	Pathogenic
31056	NM_001031679.3(MSRB3):c.55C>T (p.Arg19Ter)	Pathogenic
562077	NM_001031679.3(MSRB3):c.391-1G>A	Pathogenic
1185616	NM_001031679.3(MSRB3):c.406G>A (p.Gly136Arg)	Likely pathogenic
1324742	NM_001031679.3(MSRB3):c.-147T>G	Likely pathogenic
1473659	NM_001031679.3(MSRB3):c.185+1G>T	Likely pathogenic
228274	NM_001031679.3(MSRB3):c.264-1G>A	Likely pathogenic
3075700	NM_001031679.3(MSRB3):c.293-2A>G	Likely pathogenic
3601282	NM_001031679.3(MSRB3):c.292G>T (p.Gly98Cys)	Likely pathogenic
3601283	NM_001031679.3(MSRB3):c.449dup (p.Tyr150Ter)	Likely pathogenic

SpliceAI

2424 predictions. Top by Δscore:

Variant	Effect	Δscore
12:65280526:G:GG	donor_gain	1.0000
12:65307023:C:CG	donor_gain	1.0000
12:65307023:C:G	donor_gain	1.0000
12:65328524:A:AG	acceptor_gain	1.0000
12:65328525:G:GG	acceptor_gain	1.0000
12:65328525:GT:G	acceptor_gain	1.0000
12:65328602:AAG:A	donor_loss	1.0000
12:65328603:AGTA:A	donor_loss	1.0000
12:65328604:G:GG	donor_gain	1.0000
12:65328605:T:A	donor_loss	1.0000
12:65328606:AA:A	donor_loss	1.0000
12:65452903:G:GG	donor_gain	1.0000
12:65452940:GCCCA:G	donor_gain	1.0000
12:65463324:G:GG	donor_gain	1.0000
12:65463331:A:T	donor_gain	1.0000
12:65278861:GTCCG:G	donor_gain	0.9900
12:65278863:CCGG:C	donor_loss	0.9900
12:65278866:G:A	donor_loss	0.9900
12:65278866:G:GG	donor_gain	0.9900
12:65278867:T:G	donor_loss	0.9900
12:65280525:A:AG	donor_gain	0.9900
12:65280530:T:G	donor_gain	0.9900
12:65285077:G:GT	donor_gain	0.9900
12:65307006:G:GG	donor_gain	0.9900
12:65307022:GC:G	donor_gain	0.9900
12:65307027:G:GG	donor_gain	0.9900
12:65308046:G:GG	donor_gain	0.9900
12:65308608:TGACA:T	donor_gain	0.9900
12:65308718:G:GT	donor_gain	0.9900
12:65308719:A:T	donor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001549 (12:65441441 C>A,G,T), RS1000005883 (12:65427766 A>G), RS1000040784 (12:65384815 A>G), RS1000048495 (12:65303756 A>G), RS1000049439 (12:65390052 C>T), RS1000052247 (12:65305212 C>T), RS1000055801 (12:65402665 G>C), RS1000059666 (12:65427495 T>C), RS1000071574 (12:65454730 T>C), RS1000076007 (12:65396263 C>A,T), RS1000082169 (12:65304114 T>C), RS1000100100 (12:65390468 G>A,C,T), RS1000113781 (12:65347049 G>C), RS1000126207 (12:65317633 T>C,G), RS1000153687 (12:65360866 A>C,G)

Disease associations

OMIM: gene MIM:613719 | disease phenotypes: MIM:613718, MIM:220290, MIM:607197

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	Autosomal recessive
autosomal recessive nonsyndromic hearing loss 74	Strong	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	AR

Mondo (3): autosomal recessive nonsyndromic hearing loss 74 (MONDO:0013386), hearing loss, autosomal recessive (MONDO:0019588), nonsyndromic genetic hearing loss (MONDO:0019497)

Orphanet (3): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare genetic deafness (Orphanet:96210), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000510	Rod-cone dystrophy
HP:0003577	Congenital onset

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST000609_6	Primary tooth development (time to first tooth eruption)	6.000000e-09
GCST000610_1	Primary tooth development (number of teeth)	9.000000e-07
GCST000909_3	Type 2 diabetes nephropathy	4.000000e-06
GCST001485_2	Hippocampal volume	5.000000e-11
GCST001531_9	Temperament	2.000000e-06
GCST002030_6	Primary tooth development (time to first tooth eruption)	7.000000e-14
GCST002031_5	Primary tooth development (number of teeth)	2.000000e-09
GCST002756_11	Subcortical brain region volumes	3.000000e-07
GCST002756_7	Subcortical brain region volumes	7.000000e-11
GCST003264_871	Post bronchodilator FEV1/FVC ratio	1.000000e-06
GCST003961_2	Hippocampal volume	2.000000e-19
GCST004183_17	Lung function (FEV1)	1.000000e-09
GCST004753_3	Papillary thyroid cancer	5.000000e-07
GCST004798_4	Differentiated thyroid cancer	4.000000e-08
GCST006871_5	Total hippocampal volume	2.000000e-20
GCST006874_1	Hippocampal subfield CA1 volume (corrected for total hippocampal volume)	8.000000e-19
GCST006886_4	Subiculum volume	2.000000e-13
GCST006887_3	Hippocampal subfield CA1 volume	6.000000e-28
GCST006888_2	Hippocampal subfield CA3 volume	9.000000e-19
GCST006889_1	Hippocampal subfield CA4 volume	3.000000e-19
GCST006890_5	Dentate gyrus granule cell layer volume	5.000000e-21
GCST006891_4	Dentate gyrus molecular layer volume	6.000000e-17
GCST006892_1	Hippocampal fissure volume	2.000000e-13
GCST006979_1065	Heel bone mineral density	9.000000e-15
GCST007325_97	General risk tolerance (MTAG)	1.000000e-10
GCST007429_147	Lung function (FVC)	2.000000e-14
GCST007430_121	Peak expiratory flow	7.000000e-09
GCST007432_148	FEV1	6.000000e-15
GCST008362_46	Birth weight	6.000000e-08
GCST008711_1	Temporal lobe volume	6.000000e-10

EFO canonical traits (17, from GWAS)

EFO ID	Trait name
EFO:0005035	hippocampal volume
EFO:0004825	temperament and character inventory
EFO:0004713	FEV/FVC ratio
EFO:0004314	forced expiratory volume
EFO:0009394	hippocampal CA1 volume
EFO:0009395	hippocampal CA3 volume
EFO:0009396	hippocampal CA4 volume
EFO:0009270	heel bone mineral density
EFO:0008579	risk-taking behaviour
EFO:0004312	vital capacity
EFO:0009718	peak expiratory flow
EFO:0004344	birth weight
EFO:0007969	cognitive inhibition measurement
EFO:0004346	neuroimaging measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004531	urate measurement
EFO:0004980	appendicular lean mass

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C564609	Deafness, Autosomal Recessive (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3509604 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.00	IC50	1e+04	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 7 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179036: Inhibition of MSRB3 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression	5
trichostatin A	decreases expression, increases expression, affects cotreatment	3
sodium arsenite	decreases expression, increases abundance, increases expression	3
bisphenol A	increases methylation, increases expression	2
mercuric bromide	affects cotreatment, decreases expression	2
entinostat	decreases expression, increases expression, affects cotreatment	2
Cisplatin	affects cotreatment, decreases expression	2
Nickel	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
Particulate Matter	increases abundance, decreases expression, decreases reaction	2
triphenyl phosphate	affects expression	1
3,4-dichloroaniline	decreases expression	1
cobaltous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	affects expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
NSC 689534	affects binding, increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases abundance, increases expression	1
Vehicle Emissions	decreases expression, decreases reaction	1
Calcitriol	increases expression, affects cotreatment	1
Carbamazepine	affects expression	1
Copper	affects binding, increases expression	1
Dithiothreitol	increases reduction	1
Diuron	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 6 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3528600	ADMET	Drug metabolism assessed as human MSRB3-mediated reduced product formation	Studies on the metabolism and biological activity of the epimers of sulindac. — Drug Metab Dispos
CHEMBL5697766	Binding	Inhibition of MSRB3 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations