TMCC3

Summary

TMCC3 (transmembrane and coiled-coil domain family 3, HGNC:29199) is a protein-coding gene on chromosome 12q22, encoding Transmembrane and coiled-coil domain protein 3 (Q9ULS5).

Enables 14-3-3 protein binding activity and identical protein binding activity. Located in endoplasmic reticulum.

Source: NCBI Gene 57458 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 84 total
• MANE Select transcript: NM_020698

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29199
Approved symbol	TMCC3
Name	transmembrane and coiled-coil domain family 3
Location	12q22
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1145
Ensembl gene	ENSG00000057704
Ensembl biotype	protein_coding
OMIM	617459
Entrez	57458

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000261226, ENST00000548918, ENST00000551457, ENST00000552239, ENST00000896389

RefSeq mRNA: 2 — MANE Select: NM_020698 NM_001301036, NM_020698

CCDS: CCDS31877, CCDS73506

Canonical transcript exons

ENST00000261226 — 4 exons

Exon	Start	End
ENSE00000497628	94567122	94571737
ENSE00000817906	94578394	94578529
ENSE00001308856	94650353	94650557
ENSE00003490767	94581622	94582538

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 96.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.5607 / max 1295.4565, expressed in 1107 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
132706	5.4818	948
132705	0.8596	349
132696	0.3864	173
132703	0.3058	135
132697	0.2663	86
132704	0.1305	51
132698	0.0716	43
132699	0.0586	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
substantia nigra pars reticulata	UBERON:0001966	96.90	gold quality
substantia nigra pars compacta	UBERON:0001965	95.52	gold quality
inferior vagus X ganglion	UBERON:0005363	95.52	gold quality
jejunal mucosa	UBERON:0000399	95.16	gold quality
corpus callosum	UBERON:0002336	94.64	gold quality
subthalamic nucleus	UBERON:0001906	93.18	gold quality
medial globus pallidus	UBERON:0002477	93.11	gold quality
colonic mucosa	UBERON:0000317	92.69	gold quality
tibialis anterior	UBERON:0001385	92.53	gold quality
globus pallidus	UBERON:0001875	92.52	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.10	gold quality
endothelial cell	CL:0000115	91.76	gold quality
pigmented layer of retina	UBERON:0001782	91.40	gold quality
jejunum	UBERON:0002115	91.14	gold quality
deltoid	UBERON:0001476	90.53	gold quality
medulla oblongata	UBERON:0001896	90.51	gold quality
dorsal plus ventral thalamus	UBERON:0001897	90.31	gold quality
blood	UBERON:0000178	90.01	gold quality
ventral tegmental area	UBERON:0002691	89.66	gold quality
ileal mucosa	UBERON:0000331	89.12	gold quality
spinal cord	UBERON:0002240	88.97	gold quality
superior vestibular nucleus	UBERON:0007227	88.91	gold quality
pons	UBERON:0000988	88.88	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.74	gold quality
parietal pleura	UBERON:0002400	88.67	gold quality
midbrain	UBERON:0001891	88.61	gold quality
visceral pleura	UBERON:0002401	88.51	gold quality
substantia nigra	UBERON:0002038	88.37	gold quality
duodenum	UBERON:0002114	86.85	gold quality
lateral globus pallidus	UBERON:0002476	86.75	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	8.37
E-ANND-3	yes	5.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

194 targeting TMCC3, 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-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872

Literature-anchored findings (GeneRIF, showing 3)

• TMCC3 proteins are localized in endoplasmic reticulum through transmembrane domains and polymerized with other TMCC3 protein an 1-3-3 proteins. (PMID:27697108)
• A TMCC3 mutant lacking the N-terminal coiled-coil domain abolished localization to tubular network of the endoplasmic reticulum, suggesting that TMCC3 localized independently of binding to atlastins. (PMID:31696206)
• Transmembrane and coiled-coil domain family 3 (TMCC3) regulates breast cancer stem cell and AKT activation. (PMID:33742122)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmcc3	ENSDARG00000045525
mus_musculus	Tmcc3	ENSMUSG00000020023
rattus_norvegicus	Tmcc3	ENSRNOG00000007713
drosophila_melanogaster	Dmtn	FBGN0037443
caenorhabditis_elegans		WBGENE00015800

Paralogs (3): TMCC2 (ENSG00000133069), TMCC1 (ENSG00000172765), TEX28 (ENSG00000278057)

Protein

Protein identifiers

Transmembrane and coiled-coil domain protein 3 — Q9ULS5 (reviewed: Q9ULS5)

All UniProt accessions (3): Q9ULS5, F8VQF2, G3V207

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. May form homodimers and heterodimers with TMCC2 or TMCC3 via the coiled-coil domains. Interacts with ribosomal proteins RPL4 and RPS6.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Widely expressed, with highest levels in brain, spinal cord and testis.

Similarity. Belongs to the TEX28 family.

RefSeq proteins (2): NP_001287965, NP_065749* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019394	TEX28/TMCC	Family

Pfam: PF10267

UniProt features (13 total): transmembrane region 2, sequence variant 2, region of interest 2, coiled-coil region 2, modified residue 2, chain 1, sequence conflict 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULS5-F1	70.84	0.38

Functional residue map

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

Post-translational modifications (2): 46, 253

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 235 (showing top): MARTINEZ_RB1_TARGETS_UP, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, FOSTER_TOLERANT_MACROPHAGE_DN, SABATES_COLORECTAL_ADENOMA_DN, CUI_TCF21_TARGETS_2_DN, DELASERNA_MYOD_TARGETS_UP, MODULE_48, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, MODULE_95, TGCCTTA_MIR124A, chr12q22, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, OSMAN_BLADDER_CANCER_DN, GRYDER_PAX3FOXO1_TOP_ENHANCERS, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK

GO Biological Process (0):

GO Molecular Function (3): identical protein binding (GO:0042802), 14-3-3 protein binding (GO:0071889), protein binding (GO:0005515)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), endomembrane system (GO:0012505), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	2
cellular anatomical structure	2
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

606 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMCC3	TMTC4	Q5T4D3	505
TMCC3	CCDC106	Q9BWC9	451
TMCC3	CLEC17A	Q6ZS10	445
TMCC3	TMTC2	Q8N394	439
TMCC3	LSMEM1	Q8N8F7	431
TMCC3	RSPRY1	Q96DX4	397
TMCC3	C3orf62	Q6ZUJ4	396
TMCC3	CGGBP1	Q9UFW8	393
TMCC3	TSPAN15	O95858	386
TMCC3	TMEM209	Q96SK2	384
TMCC3	ERMN	Q8TAM6	380
TMCC3	UBE2L5	A0A1B0GUS4	379
TMCC3	PPP4R4	Q6NUP7	376
TMCC3	NUDT13	Q86X67	374
TMCC3	JAKMIP3	Q5VZ66	356

IntAct

48 interactions, top by confidence:

A	B	Type	Score
TEX28	TMCC3	psi-mi:“MI:0915”(physical association)	0.800
FBXO28	TRAF5	psi-mi:“MI:0914”(association)	0.740
ENO1	ENO2	psi-mi:“MI:0914”(association)	0.710
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
TEX28	TMCC2	psi-mi:“MI:0914”(association)	0.640
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
SLC16A3	CASK	psi-mi:“MI:0914”(association)	0.590
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
ATP6V0A2	B4GALT3	psi-mi:“MI:0914”(association)	0.530
SLC30A2	ESYT2	psi-mi:“MI:0914”(association)	0.530
TMCC3	rstB	psi-mi:“MI:0915”(physical association)	0.370
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
TEX28	NBAS	psi-mi:“MI:0914”(association)	0.350
FBXO28	EML1	psi-mi:“MI:0914”(association)	0.350
HCN1	USP27X	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
CYB5B	QSOX1	psi-mi:“MI:0914”(association)	0.350
TMCC3	HSBP1	psi-mi:“MI:0914”(association)	0.350
HTR1B	SCAMP2	psi-mi:“MI:0914”(association)	0.350
TEX28	PRAF2	psi-mi:“MI:0914”(association)	0.350
SLC19A2	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC2A5	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC30A5	NBAS	psi-mi:“MI:0914”(association)	0.350
SLC30A7	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (56): TMCC3 (Affinity Capture-MS), TMCC3 (Affinity Capture-MS), TMCC3 (Affinity Capture-MS), TMCC3 (Affinity Capture-RNA), TEX28 (Two-hybrid), TMCC3 (Affinity Capture-MS), TMCC3 (Proximity Label-MS), TMCC3 (Proximity Label-MS), TMCC3 (Proximity Label-MS), TMCC3 (Proximity Label-MS), TMCC3 (Proximity Label-MS), TMCC3 (Proximity Label-MS), TMCC3 (Proximity Label-MS), TMCC3 (Affinity Capture-RNA), TMCC3 (Reconstituted Complex)

ESM2 similar proteins: A0A1L8GXY6, A0M8S4, A1YB07, A2A6T1, A4IIE8, B3DGU2, D3YV10, E9Q9R9, G9G127, O35550, O35551, O75334, Q07DY4, Q07E41, Q09YG9, Q09YI1, Q09YK4, Q13136, Q15276, Q2IBE6, Q2QLF8, Q2VUH7, Q3LGD4, Q3TDD9, Q5U465, Q5U4W1, Q5ZJA3, Q66KE8, Q6DIS8, Q6GNW0, Q6NRB0, Q6NZT2, Q6P402, Q86YS3, Q8BQP8, Q8CFC9, Q8IYE1, Q8IZ41, Q8R310, Q8TDM6

Diamond homologs: O75069, O94876, Q69ZZ6, Q80W04, Q8R310, Q9ULS5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 45 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
Activation of BAD and translocation to mitochondria	7	166.5×	4e-13
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	146.9×	6e-13
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	146.9×	6e-13
Activation of BH3-only proteins	7	108.6×	6e-12
RHO GTPases activate PKNs	7	69.4×	2e-10
Intrinsic Pathway for Apoptosis	7	64.0×	3e-10
FOXO-mediated transcription	5	52.5×	4e-07
SARS-CoV-1-host interactions	7	38.4×	9e-09

GO biological processes:

GO term	Partners	Fold	FDR
intracellular zinc ion homeostasis	5	58.7×	3e-06
protein targeting	5	44.7×	8e-06
intracellular protein localization	8	20.4×	1e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	75
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1495 predictions. Top by Δscore:

Variant	Effect	Δscore
12:94578389:GGTAC:G	donor_loss	1.0000
12:94578390:GTA:G	donor_loss	1.0000
12:94578391:TA:T	donor_loss	1.0000
12:94578392:A:AT	donor_loss	1.0000
12:94578529:CC:C	acceptor_loss	1.0000
12:94578530:C:A	acceptor_loss	1.0000
12:94581631:T:A	donor_gain	1.0000
12:94582535:CTAC:C	acceptor_gain	1.0000
12:94582536:TAC:T	acceptor_gain	1.0000
12:94582537:AC:A	acceptor_gain	1.0000
12:94582538:CC:C	acceptor_gain	1.0000
12:94582539:C:CC	acceptor_gain	1.0000
12:94598633:C:CA	donor_gain	1.0000
12:94650348:CTCA:C	donor_loss	1.0000
12:94650349:TCA:T	donor_loss	1.0000
12:94650350:CACCC:C	donor_loss	1.0000
12:94650351:A:AC	donor_gain	1.0000
12:94650351:AC:A	donor_gain	1.0000
12:94650352:C:CC	donor_gain	1.0000
12:94650352:CC:C	donor_gain	1.0000
12:94650352:CCCGG:C	donor_gain	1.0000
12:94575148:C:A	donor_gain	0.9900
12:94578417:AGG:A	donor_gain	0.9900
12:94578525:CATAC:C	acceptor_gain	0.9900
12:94578529:CCTT:C	acceptor_gain	0.9900
12:94578532:T:C	acceptor_gain	0.9900
12:94578532:T:TC	acceptor_gain	0.9900
12:94581610:A:AC	donor_gain	0.9900
12:94581611:C:CC	donor_gain	0.9900
12:94581617:AATAC:A	donor_loss	0.9900

AlphaMissense

3154 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:94578488:A:G	L346P	0.999
12:94578497:A:G	L343P	0.999
12:94578506:A:G	L340P	0.999
12:94581969:G:C	S216R	0.999
12:94581969:G:T	S216R	0.999
12:94581971:T:G	S216R	0.999
12:94581988:A:T	I210N	0.999
12:94582272:A:C	F115L	0.999
12:94582272:A:T	F115L	0.999
12:94582274:A:G	F115L	0.999
12:94582327:A:G	L97P	0.999
12:94582331:A:C	Y96D	0.999
12:94578464:A:G	L354P	0.998
12:94578518:A:G	L336P	0.998
12:94581988:A:G	I210T	0.998
12:94582231:A:G	L129P	0.998
12:94582273:A:G	F115S	0.998
12:94582330:T:G	Y96S	0.998
12:94582331:A:G	Y96H	0.998
12:94581640:A:G	L326P	0.997
12:94581973:C:T	G215D	0.997
12:94581988:A:C	I210S	0.997
12:94581997:G:T	A207D	0.997
12:94582273:A:C	F115C	0.997
12:94582281:C:A	K112N	0.997
12:94582281:C:G	K112N	0.997
12:94582321:A:G	L99P	0.997
12:94571587:A:G	C428R	0.996
12:94578452:A:G	L358P	0.996
12:94581964:T:A	D218V	0.996

dbSNP variants (sampled 300 via entrez): RS1000006456 (12:94634474 G>A,C), RS1000009956 (12:94640662 T>C), RS1000029770 (12:94584648 C>T), RS1000038086 (12:94626555 A>G), RS1000097715 (12:94646196 G>T), RS1000155113 (12:94621800 C>T), RS1000155763 (12:94634103 C>T), RS1000247878 (12:94617399 G>T), RS1000258681 (12:94590811 G>A,C), RS1000280381 (12:94603886 T>C), RS1000353010 (12:94605849 TC>T), RS1000389795 (12:94611342 T>A), RS1000404988 (12:94643709 A>G), RS1000408465 (12:94569834 T>C), RS1000429162 (12:94637440 C>G,T)

Disease associations

OMIM: gene MIM:617459 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): myoepithelial tumor (MONDO:0002380)

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003075_17	Cognitive decline rate in late mild cognitive impairment	9.000000e-07
GCST005184_9	Common carotid intima-media thickness in HIV infection	1.000000e-06
GCST005222_4	Insulin disposition index	3.000000e-06
GCST009798_83	Asthma	6.000000e-11
GCST90002383_11	Hematocrit	5.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement
EFO:0006832	disposition index measurement
EFO:0004348	hematocrit

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009208	Myoepithelioma	C04.557.435.585

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
trichostatin A	increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
3,4-dichloroaniline	increases expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
nickel sulfate	increases expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
tacedinaline	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
abrine	decreases expression	1
dorsomorphin	increases expression, affects cotreatment, decreases expression	1
mocetinostat	increases expression	1
enzalutamide	decreases expression, increases reaction	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Bleomycin	decreases expression	1
Calcitriol	increases expression, affects cotreatment	1
Camptothecin	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TS71	HAP1 TMCC3 (-) 1	Cancer cell line	Male
CVCL_XU31	HAP1 TMCC3 (-) 2	Cancer cell line	Male
CVCL_XU32	HAP1 TMCC3 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT05266196	PHASE1/PHASE2	UNKNOWN	A Rollover Protocol to Allow for Continued Access to the LSD1 Inhibitor Seclidemstat (SP-2577)
NCT06239272	PHASE1/PHASE2	RECRUITING	NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
NCT06625190	PHASE1/PHASE2	RECRUITING	Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors
NCT06244420	Not specified	COMPLETED	Malignant Myoepithelioma of Bone and Soft Tissues: Diagnostic Imaging and Histology in Relation to Prognosis