OTOA

protein-coding

otoancorin

Gene summary

The protein encoded by this gene is specifically expressed in the inner ear, and is located at the interface between the apical surface of the inner ear sensory epithelia and their overlying acellular gels. It is prposed that this protein is involved in the attachment of the inner ear acellular gels to the apical surface of the underlying nonsensory cells. Mutations in this gene are associated with autosomal recessive deafness type 22 (DFNB22). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

Previous symbols:

DFNB22

MANE transcript

NM_144672.4

Inheritance

ClinVar variants

P:93U:212B:192

Top phenotype

Deafness, autosomal recessive 22

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr16:21,663,968-21,761,935

External References & Databases

Ensembl (ENSG00000155719)

Transcript & Mutation Effects

hg38 • Region Span ~98.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 22STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011762

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 22LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011762

Submitter: G2P

autosomal recessive nonsyndromic hearing loss 22STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011762

Submitter: Labcorp Genetics (formerly Invitae)

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The relationship between OTOA and autosomal recessive nonsyndromic hearing loss was evaluated using the ClinGen Clinical Validity Framework as of 11/10/2017. Variants in OTOA were first reported in humans with this disease as early as 2002 (Zwaenepoel et al.). At least 10 variants (e.g. missense, splice-site, large deletion, whole gene deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level, case-control, and experimental data. Variants in this gene have been reported in at least 9 probands in 6 publications (PMIDs: 11972037, 19888295, 23173898, 16460646, 26029705, 26969326). Variants in this gene segregated with disease in at least 17 additional family members. This gene-disease relationship has been studied in at least 1 case-control studies (PMID 25528277) at the aggregate variant level. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by a relevant expression studies as well as a knockout mouse model. OTOA also has a pseudogene, which could contaminate the sequencing of the gene. Caution should be used when assessing the missense variants reported in OTOA, because they could be in the pseudogene. In summary, OTOA is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 5/1/2018.

autosomal recessive nonsyndromic hearing loss 22DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011762

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 22AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

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

Refs: 11972037; 19888295

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OTOA variants in ClinVar

15 Conditions Cataloged

not providedTotal: 585

Inborn genetic diseasesTotal: 116

not specifiedTotal: 63

Autosomal recessive nonsyndromic hearing loss 22Total: 56

OTOA-related disorderTotal: 23

Rare genetic deafnessTotal: 9

Hearing impairmentTotal: 4

Monogenic hearing lossTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_144672.4. 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			3 clinvar	173 clinvar	3 clinvar	179
missense		16 clinvar	208 clinvar	16 clinvar		240
nonsense	12 clinvar	6 clinvar	1 clinvar			19
start loss						0
frameshift	28 clinvar	10 clinvar				38
splice donor/acceptor (+/-2bp)	5 clinvar	16 clinvar				21
Total	45	48	212	189	3	497

Highest pathogenic variant AF is 0.0035015864

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_144672.4	RefSeq	NP_653273.3	28	MANE Select
ENST00000646100.2	Ensembl	ENSP00000496564.2	28	MANE Select
NM_001161683.2	RefSeq	NP_001155155.1	24	Standard
NM_170664.3	RefSeq	NP_733764.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational modification: synthesis of GPI-anchored proteins
Post-translational protein modification
Metabolism of proteins

Biological Process

cell-matrix adhesion
sensory perception of sound
transmission of nerve impulse

Cellular Component

extracellular region
plasma membrane
cell surface
apical plasma membrane
anchored component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000388958
Coding exons: 28
Length: 82216
Individuals with no LoFs: 125622
Homozygous LoFs: 1
Heterozygous LoFs: 125
Defined: 125748
p: 0.000501

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.281	463	480	0.964	0.0000263	7383
Missense (PolyPhen)		121	139.03	0.87034		2507
Synonymous	0.507	191	200	0.954	0.0000117	2262
Loss of Function	3.29	24	48.8	0.492	0.00000240	700

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00018	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00065	0.00065	rare
Finnish	0.00032	0.00032	rare
European (Non-Finnish)	0.00068	0.00067	rare
South Asian	0.00056	0.00056	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May act as an adhesion molecule.;
Disease: DISEASE: Deafness, autosomal recessive, 22 (DFNB22) [MIM:607039]: 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. {ECO:0000269|PubMed:11972037}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0953

Intolerance Scores

LoFtool: 0.616
RVIS EVS: -0.82
RVIS percentile EVS: 11.98

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.350

Gene Damage Prediction

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