TMC1

transmembrane channel like 1, the group of Transmembrane channel like family

Basic information

Region (hg38): 9:72521607-72838297

Previous symbols: [ "DFNA36", "DFNB7", "DFNB11" ]

Links

ENSG00000165091 ∙ NCBI:117531 ∙ OMIM:606706 ∙ HGNC:16513 ∙ Uniprot:Q8TDI8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant nonsyndromic hearing loss 36 (Strong), mode of inheritance: AR
• autosomal recessive nonsyndromic hearing loss 7 (Strong), mode of inheritance: AD
• autosomal dominant nonsyndromic hearing loss (Supportive), mode of inheritance: AD
• hearing loss, autosomal recessive (Supportive), mode of inheritance: AR
• nonsyndromic genetic hearing loss (Strong), mode of inheritance: Semidominant
• autosomal dominant nonsyndromic hearing loss 36 (Strong), mode of inheritance: AD
• autosomal recessive nonsyndromic hearing loss 7 (Strong), mode of inheritance: AR
• autosomal recessive nonsyndromic hearing loss 7 (Definitive), mode of inheritance: AR
• nonsyndromic genetic hearing loss (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Deafness, autosomal recessive 7	AR	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic	11850618; 17250663; 18616530; 23226338; 24827932; 34523024

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TMC1 gene.

• not provided (355 variants)
• Autosomal recessive nonsyndromic hearing loss 7 (79 variants)
• not specified (68 variants)
• Autosomal dominant nonsyndromic hearing loss 36 (64 variants)
• Inborn genetic diseases (19 variants)
• Rare genetic deafness (15 variants)
• TMC1-related condition (8 variants)
• Hearing loss, autosomal recessive (5 variants)
• Hearing impairment (4 variants)
• Nonsyndromic Hearing Loss, Dominant (3 variants)
• Autosomal recessive nonsyndromic hearing loss 7;Autosomal dominant nonsyndromic hearing loss 36 (2 variants)
• Nonsyndromic genetic hearing loss (2 variants)
• Autosomal dominant nonsyndromic hearing loss 36;Autosomal recessive nonsyndromic hearing loss 7 (2 variants)
• Nonsyndromic Hearing Loss, Recessive (2 variants)
• TMC1-Related Disorders (1 variants)
• - (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 TMC1 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			4	52	1	57
missense	6	7	132	2	1	148
nonsense	14	4	1			19
start loss						0
frameshift	13		2			15
inframe indel		1		1		2
splice donor/acceptor (+/-2bp)	7	8	1			16
splice region		1	8	11		20
non coding			15	81	51	147
Total	40	20	155	136	53

Highest pathogenic variant AF is 0.000289

Variants in TMC1

This is a list of pathogenic ClinVar variants found in the TMC1 region.

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

Position	Type	Phenotype	Significance	ClinVar
9-72521801-C-T		Autosomal recessive nonsyndromic hearing loss 7 • Autosomal dominant nonsyndromic hearing loss 36	Benign/Likely benign (Jan 12, 2018)
9-72521860-T-C		Autosomal recessive nonsyndromic hearing loss 7 • Autosomal dominant nonsyndromic hearing loss 36	Uncertain significance (Jan 13, 2018)
9-72521873-G-A		Autosomal dominant nonsyndromic hearing loss 36 • Autosomal recessive nonsyndromic hearing loss 7	Benign (Jan 13, 2018)
9-72521899-T-G		Autosomal dominant nonsyndromic hearing loss 36 • Autosomal recessive nonsyndromic hearing loss 7	Uncertain significance (Jan 13, 2018)
9-72577944-G-A		Autosomal recessive nonsyndromic hearing loss 7 • Autosomal dominant nonsyndromic hearing loss 36	Uncertain significance (Apr 27, 2017)
9-72577979-C-T		Autosomal dominant nonsyndromic hearing loss 36 • Autosomal recessive nonsyndromic hearing loss 7	Uncertain significance (Jan 13, 2018)
9-72578000-C-A		Autosomal dominant nonsyndromic hearing loss 36 • Autosomal recessive nonsyndromic hearing loss 7	Benign (Jan 13, 2018)
9-72616301-G-A			Benign (Nov 04, 2021)
9-72616378-A-T		Autosomal dominant nonsyndromic hearing loss 36 • Autosomal recessive nonsyndromic hearing loss 7	Uncertain significance (Jan 15, 2018)
9-72616398-G-A		Autosomal recessive nonsyndromic hearing loss 7 • Autosomal dominant nonsyndromic hearing loss 36	Conflicting classifications of pathogenicity (Jan 13, 2018)
9-72616421-C-T		Autosomal dominant nonsyndromic hearing loss 36 • Autosomal recessive nonsyndromic hearing loss 7	Uncertain significance (Jan 13, 2018)
9-72616453-C-T		Autosomal recessive nonsyndromic hearing loss 7 • Autosomal dominant nonsyndromic hearing loss 36	Uncertain significance (Jan 12, 2018)
9-72616454-A-G		Autosomal dominant nonsyndromic hearing loss 36 • Autosomal recessive nonsyndromic hearing loss 7	Benign (Jan 13, 2018)
9-72627898-AT-A			Benign (Sep 17, 2021)
9-72627992-T-C		Autosomal dominant nonsyndromic hearing loss 36 • Autosomal recessive nonsyndromic hearing loss 7	Conflicting classifications of pathogenicity (Jan 13, 2018)
9-72648633-A-ACAGGACAC			Likely benign (Dec 04, 2018)
9-72648653-C-A			Pathogenic (Jul 06, 2023)
9-72648655-C-A		not specified	Uncertain significance (Dec 31, 2013)
9-72648657-C-T			Likely benign (Jul 25, 2023)
9-72648657-C-CA		Autosomal recessive nonsyndromic hearing loss 7	Pathogenic (Feb 16, 2016)
9-72648665-G-A			Pathogenic (Oct 31, 2023)
9-72648665-G-T		Autosomal recessive nonsyndromic hearing loss 7	Pathogenic (Dec 01, 2007)
9-72648668-T-C		TMC1-related disorder	Likely benign (Jul 28, 2020)
9-72648678-C-A			Likely benign (Dec 16, 2022)
9-72648682-ACTGT-A			Likely benign (Jan 09, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TMC1	protein_coding	protein_coding	ENST00000297784	20	314551

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
9.18e-19	0.359	125549	0	199	125748	0.000792

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.858	350	398	0.879	0.0000208	5063
Missense in Polyphen		106	129.51	0.81846		1717
Synonymous	-0.256	146	142	1.03	0.00000813	1353
Loss of Function	1.69	35	47.6	0.736	0.00000265	552

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000975	0.000975
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000548	0.000544
Finnish	0.00333	0.00333
European (Non-Finnish)	0.000637	0.000633
Middle Eastern	0.000548	0.000544
South Asian	0.000524	0.000523
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Probable ion channel required for the normal function of cochlear hair cells. {ECO:0000250}.
• Disease: DISEASE: Deafness, autosomal recessive, 7 (DFNB7) [MIM:600974]: 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:11850618}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Recessive Scores

• pRec: 0.171

Intolerance Scores

• loftool: 0.819
• rvis_EVS: -0.64
• rvis_percentile_EVS: 16.68

Haploinsufficiency Scores

• pHI: 0.117
• hipred: Y
• hipred_score: 0.540
• ghis: 0.432

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.209

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tmc1
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); hearing/vestibular/ear phenotype

Gene ontology

• Biological process: detection of mechanical stimulus involved in sensory perception of sound;vestibular reflex;auditory receptor cell development;calcium ion transmembrane transport;regulation of calcium ion transmembrane transport
• Cellular component: integral component of plasma membrane;external side of plasma membrane;stereocilium tip
• Molecular function: ion channel activity;voltage-gated calcium channel activity;mechanosensitive ion channel activity