TMC3

Summary

TMC3 (transmembrane channel like 3, HGNC:22995) is a protein-coding gene on chromosome 15q25.1, encoding Transmembrane channel-like protein 3 (Q7Z5M5). Probable component of an ion channel.

Predicted to enable mechanosensitive monoatomic ion channel activity. Predicted to be involved in monoatomic ion transmembrane transport. Predicted to be located in plasma membrane.

Source: NCBI Gene 342125 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 197 total
• MANE Select transcript: NM_001080532

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22995
Approved symbol	TMC3
Name	transmembrane channel like 3
Location	15q25.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000188869
Ensembl biotype	protein_coding
OMIM	617196
Entrez	342125

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000359440, ENST00000558726, ENST00000559982

RefSeq mRNA: 1 — MANE Select: NM_001080532 NM_001080532

CCDS: CCDS45324

Canonical transcript exons

ENST00000359440 — 22 exons

Exon	Start	End
ENSE00001384219	81337846	81337924
ENSE00001391451	81349458	81349567
ENSE00001534182	81334720	81334975
ENSE00001733041	81336609	81336651
ENSE00002566570	81373989	81374213
ENSE00003473170	81358149	81358291
ENSE00003528719	81362220	81362301
ENSE00003532795	81341390	81341518
ENSE00003540478	81351694	81351841
ENSE00003550688	81343917	81344045
ENSE00003552866	81358402	81358500
ENSE00003580672	81343278	81343345
ENSE00003613797	81338655	81338780
ENSE00003613801	81359365	81359471
ENSE00003633063	81344766	81345011
ENSE00003637576	81339394	81339504
ENSE00003647490	81355725	81355768
ENSE00003678326	81368253	81368328
ENSE00003680640	81356447	81356594
ENSE00003685233	81346365	81346443
ENSE00003690184	81372591	81372737
ENSE00003849382	81331088	81333262

Expression profiles

Bgee: expression breadth broad, 82 present calls, max score 91.64.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0441 / max 13.9922, expressed in 12 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151231	0.0441	12

Top tissues by expression

118 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	91.64	silver quality
quadriceps femoris	UBERON:0001377	87.34	gold quality
cerebellar vermis	UBERON:0004720	76.11	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.22	silver quality
cortical plate	UBERON:0005343	61.18	gold quality
bone marrow cell	CL:0002092	59.65	gold quality
right uterine tube	UBERON:0001302	54.21	gold quality
bone marrow	UBERON:0002371	53.30	gold quality
colonic epithelium	UBERON:0000397	53.29	gold quality
right lobe of liver	UBERON:0001114	53.11	gold quality
muscle layer of sigmoid colon	UBERON:0035805	52.94	gold quality
liver	UBERON:0002107	52.46	gold quality
lower esophagus mucosa	UBERON:0035834	51.13	gold quality
duodenum	UBERON:0002114	51.08	gold quality
placenta	UBERON:0001987	50.67	gold quality
prefrontal cortex	UBERON:0000451	49.47	gold quality
primary visual cortex	UBERON:0002436	49.41	silver quality
sural nerve	UBERON:0015488	48.84	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	48.30	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	48.27	gold quality
lower esophagus muscularis layer	UBERON:0035833	48.20	gold quality
lower esophagus	UBERON:0013473	48.13	gold quality
ganglionic eminence	UBERON:0004023	47.49	gold quality
colon	UBERON:0001155	47.43	gold quality
vermiform appendix	UBERON:0001154	47.34	gold quality
fallopian tube	UBERON:0003889	47.21	gold quality
ventricular zone	UBERON:0003053	47.03	silver quality
cerebellum	UBERON:0002037	46.73	silver quality
cerebellar cortex	UBERON:0002129	46.72	silver quality
cerebellar hemisphere	UBERON:0002245	46.63	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.67
E-MTAB-7249	no	60.20

Regulation

Is transcription factor: no

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:dkey-15b23.3	ENSDARG00000090696
mus_musculus	Tmc3	ENSMUSG00000038540
rattus_norvegicus	Tmc3	ENSRNOG00000025088
drosophila_melanogaster	Tmc	FBGN0267796

Paralogs (7): TMC5 (ENSG00000103534), TMC6 (ENSG00000141524), TMC2 (ENSG00000149488), TMC1 (ENSG00000165091), TMC4 (ENSG00000167608), TMC8 (ENSG00000167895), TMC7 (ENSG00000170537)

Protein

Protein identifiers

Transmembrane channel-like protein 3 — Q7Z5M5 (reviewed: Q7Z5M5)

All UniProt accessions (2): Q7Z5M5, H0YK69

UniProt curated annotations — full annotation on UniProt →

Function. Probable component of an ion channel. Molecular function hasn’t been characterized yet.

Subcellular location. Membrane.

Similarity. Belongs to the TMC family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7Z5M5-1	1	yes
Q7Z5M5-2	2

RefSeq proteins (1): NP_001074001* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012496	TMC_dom	Domain
IPR038900	TMC	Family

Pfam: PF07810

UniProt features (39 total): topological domain 11, transmembrane region 10, sequence conflict 5, sequence variant 4, region of interest 3, compositionally biased region 2, splice variant 2, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z5M5-F1	59.93	0.07

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (1): 264

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 26 (showing top): GCANCTGNY_MYOD_Q6, RGAGGAARY_PU1_Q6, GOBP_TRANSMEMBRANE_TRANSPORT, E4BP4_01, GOMF_GATED_CHANNEL_ACTIVITY, GEORGES_TARGETS_OF_MIR192_AND_MIR215, GOMF_PASSIVE_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOMF_TRANSPORTER_ACTIVITY, GOMF_MECHANOSENSITIVE_MONOATOMIC_ION_CHANNEL_ACTIVITY, GOMF_MONOATOMIC_ION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GSE13522_CTRL_VS_T_CRUZI_Y_STRAIN_INF_SKIN_IFNG_KO_DN, STAT4_01, DESCARTES_FETAL_HEART_VISCERAL_NEURONS, DESCARTES_FETAL_INTESTINE_ENS_NEURONS, DESCARTES_FETAL_PANCREAS_ENS_NEURONS

GO Biological Process (1): monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (1): mechanosensitive monoatomic ion channel activity (GO:0008381)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic ion transport	1
transmembrane transport	1
monoatomic ion channel activity	1
gated channel activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

508 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMC3	OR6K6	Q8NGW6	512
TMC3	ZNF343	Q6P1L6	506
TMC3	STT3A	P46977	454
TMC3	UTS2B	Q765I0	436
TMC3	LHFPL5	Q8TAF8	423
TMC3	SUMF2	Q8NBJ7	400
TMC3	UNC5CL	Q8IV45	395
TMC3	NUDT8	Q8WV74	371
TMC3	FYB2	Q5VWT5	370
TMC3	TLNRD1	Q9H1K6	367
TMC3	PCDH15	Q96QU1	360
TMC3	CCDC82	Q8N4S0	357
TMC3	MYO6	Q9UM54	324
TMC3	RNF141	Q8WVD5	322
TMC3	PIEZO2	Q9H5I5	319

IntAct

0 interactions, top by confidence:

BioGRID (2): TMC3 (Affinity Capture-MS), TMC3 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A0U1QT59, A2VEY9, A8X9H4, D3KZG3, O35412, O35607, O57474, O61366, O93383, P18861, P29415, P34535, P36383, P43322, P49414, P50605, P60571, P91682, Q02297, Q03345, Q05199, Q11069, Q13873, Q14693, Q2THW7, Q2THW9, Q2THX1, Q5R838, Q5RJX2, Q5YCC7, Q64448, Q69ZW3, Q6DR98, Q6H1V1, Q6IMP4, Q6TYA8, Q7TQ69, Q7Z5M5, Q86B91, Q8INR6

Diamond homologs: D3KZG3, E7FFT2, F1QFU0, F1QZE9, Q11069, Q32NZ6, Q4R7U0, Q5M7W4, Q5YCC7, Q6UXY8, Q7TN58, Q7TQ69, Q7Z402, Q7Z5M5, Q8C428, Q8R4P4, Q8TDI7, A0A0U1QT59, Q8R4P5, Q8TDI8, Q7TN60, Q7Z403

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

197 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	172
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2989 predictions. Top by Δscore:

Variant	Effect	Δscore
15:81334848:C:CA	donor_gain	1.0000
15:81336606:TACCT:T	donor_loss	1.0000
15:81336607:ACCT:A	donor_loss	1.0000
15:81336608:C:CG	donor_loss	1.0000
15:81338646:GGTAC:G	donor_loss	1.0000
15:81338647:GTAC:G	donor_loss	1.0000
15:81338648:TAC:T	donor_loss	1.0000
15:81338649:AC:A	donor_loss	1.0000
15:81338650:CT:C	donor_loss	1.0000
15:81338651:T:TA	donor_loss	1.0000
15:81338652:C:CG	donor_loss	1.0000
15:81338653:A:AC	donor_gain	1.0000
15:81338653:ACA:A	donor_loss	1.0000
15:81338654:C:CG	donor_gain	1.0000
15:81338654:CA:C	donor_gain	1.0000
15:81338654:CAA:C	donor_gain	1.0000
15:81338654:CAAA:C	donor_gain	1.0000
15:81338654:CAAAA:C	donor_gain	1.0000
15:81338781:C:CC	acceptor_gain	1.0000
15:81339389:CTTA:C	donor_loss	1.0000
15:81339390:TTACC:T	donor_loss	1.0000
15:81339391:TACC:T	donor_loss	1.0000
15:81339392:A:C	donor_loss	1.0000
15:81339393:C:CA	donor_loss	1.0000
15:81339502:GATC:G	acceptor_loss	1.0000
15:81339503:ATCT:A	acceptor_loss	1.0000
15:81339504:TCTGC:T	acceptor_loss	1.0000
15:81339505:CT:C	acceptor_loss	1.0000
15:81339506:T:A	acceptor_loss	1.0000
15:81343274:CTA:C	donor_loss	1.0000

AlphaMissense

7273 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:81351778:G:C	S333R	1.000
15:81351778:G:T	S333R	1.000
15:81351780:T:G	S333R	1.000
15:81358169:G:C	S241R	1.000
15:81358169:G:T	S241R	1.000
15:81358171:T:G	S241R	1.000
15:81341468:A:G	L589P	0.999
15:81341479:G:C	N585K	0.999
15:81341479:G:T	N585K	0.999
15:81343288:C:G	G569R	0.999
15:81343288:C:T	G569R	0.999
15:81343308:A:G	L562P	0.999
15:81343313:A:C	N560K	0.999
15:81343313:A:T	N560K	0.999
15:81343328:G:C	F555L	0.999
15:81343328:G:T	F555L	0.999
15:81343329:A:C	F555C	0.999
15:81343329:A:G	F555S	0.999
15:81343330:A:G	F555L	0.999
15:81344032:A:G	L511P	0.999
15:81344784:C:A	W500C	0.999
15:81344784:C:G	W500C	0.999
15:81346408:A:G	L410P	0.999
15:81346410:G:C	S409R	0.999
15:81346410:G:T	S409R	0.999
15:81346412:T:G	S409R	0.999
15:81346417:A:G	L407P	0.999
15:81346419:A:C	N406K	0.999
15:81346419:A:T	N406K	0.999
15:81346432:A:G	L402P	0.999

dbSNP variants (sampled 300 via entrez): RS1000003947 (15:81341124 A>G), RS1000085876 (15:81351166 A>C), RS1000174733 (15:81335546 G>A), RS1000177469 (15:81338216 A>G), RS1000329523 (15:81373886 C>A), RS1000484050 (15:81369589 A>G), RS1000514712 (15:81369308 C>T), RS1000565776 (15:81335129 C>T), RS1000670790 (15:81375474 A>G), RS1000763888 (15:81362783 G>A), RS1000784558 (15:81368512 C>A), RS1000853042 (15:81356954 T>C), RS1000858032 (15:81368094 C>A,G), RS1000926150 (15:81356761 T>C), RS1001041510 (15:81375782 CA>C)

Disease associations

OMIM: gene MIM:617196 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002077_2	Parkinson’s disease	2.000000e-07
GCST005352_3	Paclitaxel disposition in epithelial ovarian cancer	6.000000e-06
GCST006291_62	Spherical equivalent or myopia (age of diagnosis)	2.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, decreases expression	2
butyraldehyde	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Copper	affects cotreatment, decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.