TMIE

protein-coding

transmembrane inner ear

Gene summary

This gene encodes a transmembrane inner ear protein. Studies in mouse suggest that this gene is required for normal postnatal maturation of sensory hair cells in the cochlea, including correct development of stereocilia bundles. This gene is one of multiple genes responsible for recessive non-syndromic deafness (DFNB), also known as autosomal recessive nonsyndromic hearing loss (ARNSHL), the most common form of congenitally acquired inherited hearing impairment. [provided by RefSeq, Mar 2009]

Previous symbols:

DFNB6

MANE transcript

NM_147196.3

Inheritance

ClinVar variants

P:22U:52B:20

Top phenotype

Deafness, autosomal recessive 6

gnomAD constraint

pLI —, LoF o/e 1.05

Max pathogenic AF

—

Genomic locus

chr3:46,694,528-46,710,886

External References & Databases

Ensembl (ENSG00000181585)

Transcript & Mutation Effects

hg38 • Region Span ~16.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010965

Submitter: PanelApp Australia

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The TMIE gene has been associated with autosomal recessive hearing loss using the ClinGen Clinical Validity Framework as of 8/10/2017. This association was made using case-level data and experimental evidence. At least 8 unique variants (e.g. missense, nonsense, frameshift) have been reported in humans. TMIE was first associated with this disease in humans as early as 2002 (Naz et al.). Association is seen in at least 8 or probands in 3 publications (PMIDs: 12145746, 19438934, 24416283). Variants in this gene segregated with disease in 11 additional family members. This gene-disease association is supported by expression studies, knockout mouse models, biochemical function studies, protein interaction studies and a rescue in a mouse model (PMIDs: 25467981, 25475183, 19934034, 12140191). In summary, TMIE is definitively associated with autosomal recessive non-syndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 9/29/2017.

autosomal recessive nonsyndromic hearing loss 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010965

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 6MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0010965

Submitter: Ambry Genetics

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 6AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

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

Refs: 12145746; 19438934

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMIE variants in ClinVar

10 Conditions Cataloged

not providedTotal: 71

Inborn genetic diseasesTotal: 29

Autosomal recessive nonsyndromic hearing loss 6Total: 28

not specifiedTotal: 23

TMIE-related disorderTotal: 18

Sensorineural hearing loss disorderTotal: 3

Rare genetic deafnessTotal: 2

Hearing loss, autosomal recessiveTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_147196.3. 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			3 clinvar	15 clinvar		18
missense	1 clinvar	6 clinvar	47 clinvar	5 clinvar		59
nonsense	2 clinvar	1 clinvar				3
start loss	1 clinvar					1
frameshift	1 clinvar	4 clinvar	2 clinvar			7
splice donor/acceptor (+/-2bp)	4 clinvar	2 clinvar				6
Total	9	13	52	20	0	94

Highest pathogenic variant AF is 0.000053351727

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_147196.3	RefSeq	NP_671729.2	4	MANE Select
ENST00000643606.3	Ensembl	ENSP00000494576.2	4	MANE Select
NM_001370524.1	RefSeq	NP_001357453.1	3	Standard
NM_001370525.1	RefSeq	NP_001357454.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

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

Gene / Model

Organism

Observed Phenotype

tmie

Danio rerio

Structure: neuromast hair cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

sensory perception of sound
inner ear morphogenesis

Cellular Component

integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000326431
Coding exons: 4
Length: 9554
Individuals with no LoFs: 124840
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 124858
p: 0.0000721

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0515	74	75.3	0.983	0.00000513	993
Missense (PolyPhen)		31	32.024	0.96802		287
Synonymous	0.867	25	31.2	0.802	0.00000211	316
Loss of Function	-0.114	6	5.71	1.05	3.31e-7	80

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000056	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.00016	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Unknown. The protein may play some role in a cellular membrane location. May reside within an internal membrane compartment and function in pathways such as those involved in protein and/or vesicle trafficking. Alternatively, the mature protein may be localized in the plasma membrane and serve as a site of interaction for other molecules through its highly charged C-terminal domain.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.493
RVIS EVS: -0.16
RVIS percentile EVS: 41.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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