MSRB3

protein-coding

methionine sulfoxide reductase B3

Gene summary

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]

Previous symbols:

DFNB74

MANE transcript

NM_001031679.3

Inheritance

ClinVar variants

P:11U:42B:26

Top phenotype

Deafness, autosomal recessive 74

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr12:65,278,643-65,491,430

External References & Databases

Ensembl (ENSG00000174099)

Transcript & Mutation Effects

hg38 • Region Span ~212.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 74MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013386

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 74STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013386

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 74STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013386

Submitter: Labcorp Genetics (formerly Invitae)

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The MSRB3 gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 9/21/21. This association was made using case-level data and experimental evidence. At least four variants (missense, nonsense and splice-site) have been reported in humans. MSRB3 was first associated with this disease in humans as early as 2011 (Ahmed et al. 2011; PMID: 21185009). Association is seen in at least 8 probands in 2 publications and unpublished clinical data (PMIDs: 21185009, 30303587, Mass General Brigham LMM unpublished internal data, SCV000271241.2). The Mass General Brigham LMM has reported one case with profound congenital hearing loss and a novel homozygous splice variant in MSRB3 (ClinVar ID: 228274, SCV000271241.2). Variants in this gene segregated with disease in at least 6 families. This gene-disease association is supported by a null mouse model, rescue in mice ears, biochemical function, and two expression studies. In summary, there is definitive evidence to support this gene-disease association. This gene-disease pair was originally evaluated by the Hearing Loss Gene Curation Expert Panel on 11/15/2017. It was reevaluated on 9/21/2021 (SOP v8). As a result of this reevaluation, the classification changed from Moderate to Definitive, based on new literature and new SOP scoring.

autosomal recessive nonsyndromic hearing loss 74STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013386

Submitter: G2P

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 74AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 19650862; 21185009

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MSRB3 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 75

Inborn genetic diseasesTotal: 25

not specifiedTotal: 16

Autosomal recessive nonsyndromic hearing loss 74Total: 12

MSRB3-related disorderTotal: 8

Rare genetic deafnessTotal: 1

Hearing lossTotal: 1

Hearing loss, autosomal recessiveTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001031679.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	23 clinvar	1 clinvar	25
missense		3 clinvar	41 clinvar	2 clinvar		46
nonsense	1 clinvar	1 clinvar				2
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar				5
Total	2	9	42	25	1	79

Highest pathogenic variant AF is 0.000041561263

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 59 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001031679.3	RefSeq	NP_001026849.1	6	MANE Select
ENST00000308259.10	Ensembl	ENSP00000312274.6	6	MANE Select
NM_001193460.2	RefSeq	NP_001180389.1	6	Standard
NM_001193461.2	RefSeq	NP_001180390.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
msrb3	Danio rerio	Structure: neuromast hair cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

msrb3

Danio rerio

Structure: neuromast hair cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

S-Adenosylhomocysteine (SAH) Hydrolase Deficiency
Methionine Metabolism
Methionine Adenosyltransferase Deficiency
Glycine N-methyltransferase Deficiency
Hypermethioninemia

Biological Process

protein repair
cellular response to oxidative stress
oxidation-reduction process

Molecular Function

protein binding
zinc ion binding
peptide-methionine (R)-S-oxide reductase activity
L-methionine-(R)-S-oxide reductase activity

Cellular Component

mitochondrion
endoplasmic reticulum
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000355192
Coding exons: 6
Length: 209602
Individuals with no LoFs: 125735
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125748
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.313	100	109	0.916	0.00000594	1242
Missense (PolyPhen)		32	44.665	0.71644		521
Synonymous	-0.210	49	47.2	1.04	0.00000302	379
Loss of Function	1.25	5	9.07	0.551	3.83e-7	115

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the reduction of free and protein-bound methionine sulfoxide to methionine. Isoform 2 is essential for hearing. {ECO:0000269|PubMed:14699060, ECO:0000269|PubMed:21185009}.;

Recessive Scores

pRec: 0.120

Intolerance Scores

LoFtool: 0.689
RVIS EVS: -0.45
RVIS percentile EVS: 24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.948

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium