OTOF

otoferlin, the group of Ferlin family

Basic information

Region (hg38): 2:26457203-26558756

Previous symbols: [ "DFNB9" ]

Links

ENSG00000115155 ∙ NCBI:9381 ∙ OMIM:603681 ∙ HGNC:8515 ∙ Uniprot:Q9HC10 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hearing loss, autosomal recessive (Supportive), mode of inheritance: AR
• autosomal recessive nonsyndromic hearing loss 9 (Strong), mode of inheritance: AR
• autosomal recessive nonsyndromic hearing loss 9 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Deafness, autosomal recessive 9; Neuropathy, autosomal recessive, 1	AR	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic	10192385; 12114484; 12525542; 16097006; 16371502; 19461658
Individuals with NSRAN can have normal otoacoustic emissions test, but pure-tone audiometry/ABR will show abnormalities

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the OTOF gene.

• not provided (106 variants)
• Autosomal recessive nonsyndromic hearing loss 9 (38 variants)
• Rare genetic deafness (14 variants)
• Bilateral sensorineural hearing impairment (8 variants)
• Auditory neuropathy (7 variants)
• OTOF-related disorder (4 variants)
• Nonsyndromic genetic hearing loss (4 variants)
• Hearing loss, autosomal recessive (3 variants)
• not specified (2 variants)
• Auditory neuropathy spectrum disorder (2 variants)
• Tricho-oculo-dermo-vertebral syndrome (1 variants)
• Auditory neuropathy, autosomal recessive, 1 (1 variants)
• Hearing impairment (1 variants)
• Ear malformation (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the OTOF gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			9	534	11	554
missense	6	19	299	79	13	416
nonsense	57	9		1		67
start loss				1		1
frameshift	48	18				66
inframe indel		4	5			9
splice donor/acceptor (+/-2bp)	17	43	1			61
splice region	2	2	19	94	5	122
non coding		1	22	365	86	474
Total	128	94	336	980	110

Highest pathogenic variant AF is 0.000210

Variants in OTOF

This is a list of pathogenic ClinVar variants found in the OTOF region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-26457302-C-T		Autosomal recessive nonsyndromic hearing loss 9	Uncertain significance (Jan 12, 2018)
2-26457339-A-AG		Hearing loss, autosomal recessive	Likely benign (Jun 14, 2016)
2-26457340-G-T		Autosomal recessive nonsyndromic hearing loss 9	Uncertain significance (Jan 12, 2018)
2-26457371-G-A		Autosomal recessive nonsyndromic hearing loss 9	Uncertain significance (Jan 13, 2018)
2-26457426-G-A		Autosomal recessive nonsyndromic hearing loss 9	Uncertain significance (Jan 13, 2018)
2-26457468-A-T		Autosomal recessive nonsyndromic hearing loss 9	Uncertain significance (Jan 13, 2018)
2-26457469-C-G		Autosomal recessive nonsyndromic hearing loss 9	Uncertain significance (Jan 13, 2018)
2-26457524-T-A		Autosomal recessive nonsyndromic hearing loss 9	Uncertain significance (Jan 12, 2018)
2-26457541-C-T		Autosomal recessive nonsyndromic hearing loss 9	Benign (Jan 13, 2018)
2-26457542-T-C		Autosomal recessive nonsyndromic hearing loss 9	Benign (Jan 12, 2018)
2-26457588-G-T		Autosomal recessive nonsyndromic hearing loss 9	Likely benign (Jan 12, 2018)
2-26457628-G-A		Autosomal recessive nonsyndromic hearing loss 9	Uncertain significance (Jan 13, 2018)
2-26457764-G-A		Autosomal recessive nonsyndromic hearing loss 9	Uncertain significance (Jan 12, 2018)
2-26457798-A-G		Autosomal recessive nonsyndromic hearing loss 9	Uncertain significance (Jan 12, 2018)
2-26457866-G-A		Autosomal recessive nonsyndromic hearing loss 9	Benign/Likely benign (Jul 14, 2018)
2-26457890-C-A		Autosomal recessive nonsyndromic hearing loss 9	Conflicting classifications of pathogenicity (Dec 22, 2018)
2-26457897-C-T		Autosomal recessive nonsyndromic hearing loss 9	Uncertain significance (Jan 13, 2018)
2-26458018-G-A		Autosomal recessive nonsyndromic hearing loss 9	Likely benign (Sep 16, 2018)
2-26458034-C-T		not specified	Likely benign (Sep 10, 2016)
2-26458042-A-G		Autosomal recessive nonsyndromic hearing loss 9	Pathogenic (Jul 01, 2017)
2-26458055-C-A		not specified	Uncertain significance (May 09, 2023)
2-26458059-T-C		not specified	Uncertain significance (Nov 10, 2023)
2-26458066-T-C			Uncertain significance (Feb 28, 2024)
2-26458074-G-C		Auditory neuropathy, autosomal recessive, 1	Pathogenic (Jan 01, 2003)
2-26458102-T-A			Uncertain significance (Jun 01, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
OTOF	protein_coding	protein_coding	ENST00000272371	46	101496

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.38e-39	0.220	123599	92	2057	125748	0.00858

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.288	1252	1.22e+3	1.02	0.0000851	13067
Missense in Polyphen		440	448.35	0.98138		4819
Synonymous	-1.44	550	509	1.08	0.0000374	3877
Loss of Function	2.63	76	105	0.723	0.00000565	1174

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.129	0.0977
Ashkenazi Jewish	0.00102	0.000993
East Asian	0.0125	0.0125
Finnish	0.000423	0.000416
European (Non-Finnish)	0.00194	0.00176
Middle Eastern	0.0125	0.0125
South Asian	0.000790	0.000752
Other	0.00693	0.00621

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion and in the control of neurotransmitter release at these output synapses. Interacts in a calcium-dependent manner to the presynaptic SNARE proteins at ribbon synapses of cochlear inner hair cells (IHCs) to trigger exocytosis of neurotransmitter. Also essential to synaptic exocytosis in immature outer hair cells (OHCs). May also play a role within the recycling of endosomes (By similarity). {ECO:0000250}.
• Disease: DISEASE: Deafness, autosomal recessive, 9 (DFNB9) [MIM:601071]: 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:10192385, ECO:0000269|PubMed:12127154, ECO:0000269|PubMed:16097006, ECO:0000269|PubMed:16283880, ECO:0000269|PubMed:16371502, ECO:0000269|PubMed:26437881}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Auditory neuropathy, autosomal recessive, 1 (AUNB1) [MIM:601071]: A form of sensorineural hearing loss with absent or severely abnormal auditory brainstem response, in the presence of normal cochlear outer hair cell function and normal otoacoustic emissions. Auditory neuropathies result from a lesion in the area including the inner hair cells, connections between the inner hair cells and the cochlear branch of the auditory nerve, the auditory nerve itself and auditory pathways of the brainstem. In some cases AUNB1 phenotype can be temperature sensitive. {ECO:0000269|PubMed:16371502, ECO:0000269|PubMed:18381613}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Intolerance Scores

• loftool: 0.315
• rvis_EVS: -0.11
• rvis_percentile_EVS: 45.58

Haploinsufficiency Scores

• pHI: 0.509
• hipred: N
• hipred_score: 0.475
• ghis: 0.434

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.712

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Otof
• Phenotype: hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: otofb
• Affected structure: locomotory behavior
• Phenotype tag: abnormal
• Phenotype quality: decreased process quality

Gene ontology

• Biological process: sensory perception of sound;synaptic vesicle exocytosis;membrane fusion
• Cellular component: endoplasmic reticulum membrane;cytosol;integral component of membrane;basolateral plasma membrane;cell junction;synaptic vesicle membrane
• Molecular function: molecular_function;calcium ion binding