TMCO6

Summary

TMCO6 (transmembrane and coiled-coil domains 6, HGNC:28814) is a protein-coding gene on chromosome 5q31.3, encoding Transmembrane and coiled-coil domain-containing protein 6 (Q96DC7). It is a selective cancer dependency (DepMap: 13.9% of cell lines).

Predicted to enable nuclear import signal receptor activity. Predicted to be involved in protein import into nucleus. Predicted to be located in membrane.

Source: NCBI Gene 55374 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 95 total
• Cancer dependency (DepMap): dependent in 13.9% of screened cell lines
• MANE Select transcript: NM_018502

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28814
Approved symbol	TMCO6
Name	transmembrane and coiled-coil domains 6
Location	5q31.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ39769, PRO1580
Ensembl gene	ENSG00000113119
Ensembl biotype	protein_coding
Entrez	55374

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 9 protein_coding, 6 retained_intron, 5 nonsense_mediated_decay

ENST00000252100, ENST00000394669, ENST00000394671, ENST00000504069, ENST00000505086, ENST00000509217, ENST00000509269, ENST00000509605, ENST00000510336, ENST00000511410, ENST00000513002, ENST00000514449, ENST00000515265, ENST00000515653, ENST00000876840, ENST00000876841, ENST00000876842, ENST00000876843, ENST00000934091, ENST00000934092

RefSeq mRNA: 3 — MANE Select: NM_018502 NM_001300980, NM_001300982, NM_018502

CCDS: CCDS4233, CCDS75320

Canonical transcript exons

ENST00000394671 — 12 exons

Exon	Start	End
ENSE00000973547	140644985	140645404
ENSE00001519178	140639451	140639612
ENSE00003483481	140644100	140644194
ENSE00003484094	140644573	140644740
ENSE00003500959	140643564	140643675
ENSE00003557662	140642925	140643041
ENSE00003571139	140641870	140642053
ENSE00003583487	140642315	140642419
ENSE00003599154	140643780	140643966
ENSE00003604742	140642586	140642671
ENSE00003637746	140639739	140639851
ENSE00003642564	140641665	140641780

Expression profiles

Bgee: expression breadth ubiquitous, 216 present calls, max score 93.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.3939 / max 100.8374, expressed in 1773 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
58922	11.1898	1755
58923	1.2041	746

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	93.41	gold quality
right lobe of liver	UBERON:0001114	91.82	gold quality
right adrenal gland	UBERON:0001233	89.90	gold quality
right uterine tube	UBERON:0001302	89.75	gold quality
left adrenal gland cortex	UBERON:0035825	89.59	gold quality
left adrenal gland	UBERON:0001234	89.23	gold quality
right adrenal gland cortex	UBERON:0035827	88.67	gold quality
left ovary	UBERON:0002119	88.56	gold quality
mucosa of transverse colon	UBERON:0004991	88.52	gold quality
granulocyte	CL:0000094	88.35	gold quality
right ovary	UBERON:0002118	88.30	gold quality
body of pancreas	UBERON:0001150	88.29	gold quality
minor salivary gland	UBERON:0001830	87.97	gold quality
right testis	UBERON:0004534	87.75	gold quality
adrenal cortex	UBERON:0001235	87.74	gold quality
lower esophagus mucosa	UBERON:0035834	87.45	gold quality
right lobe of thyroid gland	UBERON:0001119	87.20	gold quality
left testis	UBERON:0004533	86.84	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.63	gold quality
spleen	UBERON:0002106	86.48	gold quality
tibial nerve	UBERON:0001323	86.34	gold quality
adrenal gland	UBERON:0002369	86.31	gold quality
esophagus mucosa	UBERON:0002469	86.29	gold quality
left uterine tube	UBERON:0001303	86.17	gold quality
omental fat pad	UBERON:0010414	86.06	gold quality
ovary	UBERON:0000992	86.05	gold quality
saliva-secreting gland	UBERON:0001044	86.03	gold quality
peritoneum	UBERON:0002358	85.98	gold quality
cerebellar hemisphere	UBERON:0002245	85.96	gold quality
endocervix	UBERON:0000458	85.84	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting TMCO6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-4778-5P	97.96	68.06	1634
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-3116	97.07	65.78	1324
HSA-MIR-1236-5P	96.62	66.38	856
HSA-MIR-6822-3P	96.60	66.06	680
HSA-MIR-3654	96.43	66.55	646
HSA-MIR-7160-3P	96.40	64.15	462
HSA-MIR-769-5P	94.45	64.56	603
HSA-MIR-4765	93.11	66.17	737

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 13.9% of screened cell lines.

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmco6	ENSDARG00000016336
mus_musculus	Tmco6	ENSMUSG00000006850
rattus_norvegicus	Tmco6	ENSRNOG00000017718
drosophila_melanogaster	CG15443	FBGN0031609

Protein

Protein identifiers

Transmembrane and coiled-coil domain-containing protein 6 — Q96DC7 (reviewed: Q96DC7)

All UniProt accessions (4): D6R986, D6REQ9, D6REY4, Q96DC7

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96DC7-1	1	yes
Q96DC7-2	2

RefSeq proteins (3): NP_001287909, NP_001287911, NP_060972* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000225	Armadillo	Repeat
IPR002652	Importin-a_IBB	Domain
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily

UniProt features (7 total): transmembrane region 2, chain 1, coiled-coil region 1, splice variant 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96DC7-F1	87.22	0.75

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 111 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_NUCLEAR_TRANSPORT, BROWNE_HCMV_INFECTION_48HR_DN, BROWNE_HCMV_INFECTION_14HR_DN, WANG_CISPLATIN_RESPONSE_AND_XPC_DN, WANG_TARGETS_OF_MLL_CBP_FUSION_UP, MASSARWEH_RESPONSE_TO_ESTRADIOL, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, IK2_01, GOBP_PROTEIN_LOCALIZATION_TO_NUCLEUS, chr5q31, MOOTHA_VOXPHOS

GO Biological Process (1): protein import into nucleus (GO:0006606)

GO Molecular Function (2): nuclear import signal receptor activity (GO:0061608), protein binding (GO:0005515)

GO Cellular Component (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
import into nucleus	2
intracellular protein transport	1
protein localization to nucleus	1
establishment of protein localization to organelle	1
nucleocytoplasmic carrier activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1360 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMCO6	MISP3	Q96FF7	582
TMCO6	PDZD9	Q8IXQ8	514
TMCO6	DENND6B	Q8NEG7	449
TMCO6	ZNF791	Q3KP31	401
TMCO6	SLC9D1	Q6UWJ1	380
TMCO6	IQCE	Q6IPM2	373
TMCO6	YARS1	P54577	352
TMCO6	NAXE	Q8NCW5	325
TMCO6	GPCPD1	Q9NPB8	310
TMCO6	PMPCB	O75439	309
TMCO6	DHRS4	Q9BTZ2	303
TMCO6	STARD7	Q9NQZ5	301
TMCO6	ODAD2	Q5T2S8	293
TMCO6	SLC9A4	Q6AI14	289
TMCO6	XKR6	Q5GH73	288
TMCO6	NOSIP	Q9Y314	288

IntAct

24 interactions, top by confidence:

A	B	Type	Score
ZNF511	TMCO6	psi-mi:“MI:0915”(physical association)	0.740
TMCO6	UBQLN1	psi-mi:“MI:0915”(physical association)	0.670
UBQLN1	TMCO6	psi-mi:“MI:0915”(physical association)	0.670
LSM5	LSM1	psi-mi:“MI:0914”(association)	0.640
LSM6	PRMT5	psi-mi:“MI:0914”(association)	0.530
LSM4	RABGAP1L	psi-mi:“MI:0914”(association)	0.350
LSM7	GEMIN2	psi-mi:“MI:0914”(association)	0.350
TMCO6	UBB	psi-mi:“MI:0914”(association)	0.350
ZNF511	CYFIP1	psi-mi:“MI:0914”(association)	0.350
LSM7	SART1	psi-mi:“MI:0914”(association)	0.350
ZNF511	GNB3	psi-mi:“MI:0914”(association)	0.350
TMCO6	PSME4	psi-mi:“MI:0914”(association)	0.350
ZNF511	AZU1	psi-mi:“MI:0914”(association)	0.350
TMCO6	UBQLN1	psi-mi:“MI:0915”(physical association)	0.000
ZNF511	TMCO6	psi-mi:“MI:0915”(physical association)	0.000
UBQLN1	TMCO6	psi-mi:“MI:0915”(physical association)	0.000
TMCO6	ZNF511	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (29): TMCO6 (Two-hybrid), TMCO6 (Affinity Capture-MS), UBB (Affinity Capture-MS), CCPG1 (Affinity Capture-MS), DPP9 (Affinity Capture-MS), PHYHIPL (Affinity Capture-MS), MINPP1 (Affinity Capture-MS), TMCO6 (Two-hybrid), PHYHIPL (Affinity Capture-MS), TMCO6 (Affinity Capture-MS), TMCO6 (Affinity Capture-MS), DPP9 (Affinity Capture-MS), UBB (Affinity Capture-MS), TMCO6 (Affinity Capture-MS), UBQLN1 (Two-hybrid)

ESM2 similar proteins: A0A0B4J1F4, A0A0G2JXN2, A4FV98, A6QPA3, C9J798, C9JJ37, D3YWP0, D3ZVU9, D4A2K4, O43374, O70277, O75382, O95294, P0C6S8, P22674, P57775, Q08DS0, Q0GA42, Q3U410, Q3UGX3, Q4G0W2, Q4V892, Q5SUV1, Q5XIU1, Q6GQU6, Q6IA17, Q6PF15, Q6TDP3, Q6TDP4, Q7TNM2, Q7Z4K8, Q86WI3, Q8CIW5, Q8IZ69, Q8K430, Q8N531, Q8N8L6, Q8NE01, Q8WXI3, Q969K4

Diamond homologs: Q8BQX5, Q96DC7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA decay by 5’ to 3’ exoribonuclease	5	271.9×	5e-10
mRNA Splicing	5	39.2×	7e-06
Processing of Capped Intron-Containing Pre-mRNA	5	29.3×	2e-05
Metabolism of RNA	7	20.8×	1e-06
mRNA Splicing - Major Pathway	5	19.5×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
mRNA splicing, via spliceosome	5	30.5×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	68
Likely benign	8
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2803 predictions. Top by Δscore:

Variant	Effect	Δscore
5:140639807:G:GT	donor_gain	1.0000
5:140639820:G:T	donor_gain	1.0000
5:140641650:T:A	acceptor_gain	1.0000
5:140641655:T:TA	acceptor_gain	1.0000
5:140641658:A:AG	acceptor_gain	1.0000
5:140641660:TCCA:T	acceptor_loss	1.0000
5:140641661:CCAG:C	acceptor_loss	1.0000
5:140641663:A:AG	acceptor_gain	1.0000
5:140641664:G:GA	acceptor_loss	1.0000
5:140641664:G:GG	acceptor_gain	1.0000
5:140641664:GGT:G	acceptor_gain	1.0000
5:140641777:TCCGG:T	donor_loss	1.0000
5:140641781:G:GG	donor_gain	1.0000
5:140642054:G:GG	donor_gain	1.0000
5:140642584:A:AG	acceptor_gain	1.0000
5:140642585:G:GA	acceptor_gain	1.0000
5:140642672:G:GG	donor_gain	1.0000
5:140643778:AGCT:A	acceptor_gain	1.0000
5:140643779:GCTG:G	acceptor_gain	1.0000
5:140639579:GAGC:G	donor_gain	0.9900
5:140639582:C:G	donor_gain	0.9900
5:140639599:G:GT	donor_gain	0.9900
5:140639628:G:GT	donor_gain	0.9900
5:140639820:G:GT	donor_gain	0.9900
5:140640840:T:G	donor_gain	0.9900
5:140641115:G:T	donor_gain	0.9900
5:140641650:T:TA	acceptor_loss	0.9900
5:140641659:C:G	acceptor_gain	0.9900
5:140641663:AG:A	acceptor_gain	0.9900
5:140641663:AGGT:A	acceptor_gain	0.9900

AlphaMissense

3130 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:140641950:T:C	L132P	0.984
5:140642343:T:C	L176P	0.983
5:140643016:T:A	W261R	0.983
5:140643016:T:C	W261R	0.983
5:140643801:T:C	C314R	0.983
5:140642321:T:C	C169R	0.982
5:140642616:G:A	G212R	0.982
5:140642616:G:C	G212R	0.982
5:140639779:G:C	K42N	0.981
5:140639779:G:T	K42N	0.981
5:140642016:T:C	L154P	0.981
5:140643961:T:C	L367P	0.981
5:140641937:G:C	A128P	0.979
5:140641946:T:C	C131R	0.979
5:140642617:G:A	G212E	0.979
5:140641959:T:C	L135P	0.977
5:140642323:T:G	C169W	0.977
5:140642334:T:C	L173P	0.973
5:140643807:A:C	S316R	0.973
5:140643809:C:A	S316R	0.973
5:140643809:C:G	S316R	0.973
5:140642635:T:C	L218P	0.971
5:140642337:G:A	G174D	0.970
5:140641747:T:C	L94S	0.969
5:140643023:T:C	L263P	0.969
5:140642325:T:C	L170P	0.967
5:140643019:T:C	C262R	0.967
5:140643939:G:C	G360R	0.966
5:140641959:T:A	L135H	0.965
5:140641940:G:C	A129P	0.964

dbSNP variants (sampled 300 via entrez): RS1000028470 (5:140622901 A>G), RS1000040710 (5:140619136 A>C), RS1000048387 (5:140615820 A>C), RS1000065251 (5:140648011 T>G), RS1000088418 (5:140622588 G>A), RS1000174425 (5:140622227 A>G), RS1000264296 (5:140616848 C>T), RS1000268107 (5:140609006 A>G), RS1000337221 (5:140628883 G>A), RS1000435906 (5:140610124 G>A), RS1000447672 (5:140636107 T>C), RS1000489687 (5:140609807 T>C), RS1000581045 (5:140596327 G>T), RS1000607369 (5:140642768 T>C), RS1000719244 (5:140616612 A>G)

Disease associations

OMIM: gene `` | disease phenotypes: MIM:256000, MIM:618235, MIM:252010

GenCC curated gene-disease

Mondo (3): Leigh syndrome (MONDO:0009723), mitochondrial complex I deficiency, nuclear type 13 (MONDO:0032618), mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224)

Orphanet (1): Leigh syndrome (Orphanet:506)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004946_157	Schizophrenia	2.000000e-08
GCST006803_54	Schizophrenia	8.000000e-07
GCST009391_1529	Metabolite levels	9.000000e-06
GCST010146_22	Serum immune biomarker levels	7.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009771	methionine measurement
EFO:0004872	inflammatory biomarker measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2569190	CD14, TMCO6	3	2.25	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression	3
Air Pollutants	decreases expression, increases abundance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	decreases expression	1
N-benzyloxycarbonylprolylprolinal	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Arsenic Trioxide	decreases expression	1
Acetaminophen	decreases expression	1
Hexachlorocyclohexane	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Silicon Dioxide	decreases expression	1
Testosterone	decreases expression	1
Thiram	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells