TSPAN12

Summary

TSPAN12 (tetraspanin 12, HGNC:21641) is a protein-coding gene on chromosome 7q31.31, encoding Tetraspanin-12 (O95859). Regulator of cell surface receptor signal transduction.

The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility.

Source: NCBI Gene 23554 — RefSeq curated summary.

At a glance

• Gene–disease (curated): TSPAN12-related exudative vitreoretinopathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 309 total — 39 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 32
• MANE Select transcript: NM_012338

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21641
Approved symbol	TSPAN12
Name	tetraspanin 12
Location	7q31.31
Locus type	gene with protein product
Status	Approved
Aliases	NET-2
Ensembl gene	ENSG00000106025
Ensembl biotype	protein_coding
OMIM	613138
Entrez	23554

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 22 protein_coding, 1 nonsense_mediated_decay

ENST00000222747, ENST00000415871, ENST00000424710, ENST00000430985, ENST00000433758, ENST00000441017, ENST00000450414, ENST00000854319, ENST00000854320, ENST00000854321, ENST00000854322, ENST00000854323, ENST00000854324, ENST00000854325, ENST00000854326, ENST00000918669, ENST00000918670, ENST00000918671, ENST00000918672, ENST00000968602, ENST00000968603, ENST00000968604, ENST00000968605

RefSeq mRNA: 1 — MANE Select: NM_012338 NM_012338

CCDS: CCDS5777

Canonical transcript exons

ENST00000222747 — 8 exons

Exon	Start	End
ENSE00000718932	120840027	120840109
ENSE00000881958	120787320	120788897
ENSE00000881959	120856698	120856833
ENSE00001216373	120857820	120858144
ENSE00003481588	120810463	120810570
ENSE00003493858	120806549	120806692
ENSE00003784229	120838777	120838912
ENSE00003790365	120815729	120815803

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 97.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.5584 / max 163.3774, expressed in 1039 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85889	2.1166	774
85887	0.9408	431
85891	0.7159	264
85888	0.6213	338
85890	0.0644	26
85884	0.0493	12
85886	0.0262	15
85885	0.0237	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	97.36	gold quality
nephron tubule	UBERON:0001231	96.43	gold quality
secondary oocyte	CL:0000655	96.28	gold quality
right adrenal gland	UBERON:0001233	95.38	gold quality
adrenal tissue	UBERON:0018303	95.38	gold quality
heart right ventricle	UBERON:0002080	95.32	gold quality
lower lobe of lung	UBERON:0008949	94.70	gold quality
jejunal mucosa	UBERON:0000399	94.49	gold quality
renal glomerulus	UBERON:0000074	94.10	gold quality
metanephric glomerulus	UBERON:0004736	93.96	gold quality
metanephros	UBERON:0000081	93.92	gold quality
left adrenal gland	UBERON:0001234	93.81	gold quality
right adrenal gland cortex	UBERON:0035827	93.79	gold quality
parotid gland	UBERON:0001831	93.62	gold quality
kidney	UBERON:0002113	93.61	gold quality
kidney epithelium	UBERON:0004819	93.57	gold quality
adult mammalian kidney	UBERON:0000082	93.47	gold quality
renal medulla	UBERON:0000362	93.39	gold quality
seminal vesicle	UBERON:0000998	93.35	gold quality
adrenal gland	UBERON:0002369	93.30	gold quality
palpebral conjunctiva	UBERON:0001812	92.95	gold quality
left adrenal gland cortex	UBERON:0035825	92.71	gold quality
adrenal cortex	UBERON:0001235	92.41	gold quality
metanephros cortex	UBERON:0010533	92.41	gold quality
cortex of kidney	UBERON:0001225	91.91	gold quality
visceral pleura	UBERON:0002401	91.86	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.21	gold quality
right lung	UBERON:0002167	90.90	gold quality
colonic mucosa	UBERON:0000317	90.64	gold quality
cardiac ventricle	UBERON:0002082	90.09	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-114530	yes	480.40
E-GEOD-124472	yes	411.73
E-HCAD-10	yes	390.91
E-MTAB-5061	yes	6.42
E-MTAB-6678	no	3.04
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

131 targeting TSPAN12, 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-3064-3P	100.00	70.09	1254
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163

Literature-anchored findings (GeneRIF, showing 40)

• TSPAN12 serves as a novel and robust partner for ADAM10 and promotes ADAM10 maturation, thereby facilitating ADAM10-dependent proteolysis of APP. (PMID:19587294)
• TSPAN12 promotes Norrin/Frizzled-4 signaling during retinal vascularization. (PMID:19837033)
• Sequence analysis of TSPAN12 revealed two mutations segregating in five of 11 familial exudative vitreoretinopathy families (FEVR), indicating that mutations in TSPAN12 are a relatively frequent cause of FEVR. (PMID:20159111)
• Mutations in TSPAN12 also cause autosomal-dominant familial exudative vitreoretinopathy. (PMID:20159112)
• The results provide further evidence that mutations in TSPAN12 are familial exudative vitreoretinopathy (FEVR) causing and that the gene products most likely play a role in the development of retinal vessels. (PMID:21334594)
• TSPAN12 mutations are responsible for familial exudative vitreoretinopathy (FEVR). The phenotypes associated with TSPAN12 mutations showed great variations between different individuals within a family and between the two eyes in individual patients. (PMID:21552475)
• We speculate that haploinsufficiency of TSPAN12 contributes to PHPV. (PMID:21626674)
• The largest miRNA-146a-TSPAN12 response to stress of amyloidbeta peptide + tumor necrosis factoralpha is found in human neuronal glial cells from Alzheimer brain. (PMID:21640790)
• This study is the first report of recessive mutations in TSPAN12 and shows that patients with two mutant alleles have a severe form of FEVR or retinal dysplasia, whereas heterozygous family members have mild familial exudative vitreoretinopathy phenotypes (PMID:22427576)
• Here we describe a case of a female infant affected by cystic fibrosis and by a severe form of exudative vitreoretinopathy. In particular, we have detected the homozygous missense mutation c.668 T > C in TSPAN12. (PMID:23834558)
• TSPAN12 plays a role in supporting primary tumor growth and suppressing metastasis. (PMID:23955570)
• Novel mutation in TSPAN12 leads to autosomal recessive inheritance of congenital vitreoretinal disease with intra-familial phenotypic variability. (PMID:25250762)
• Novel mutations have been described in the TSPAN12 gene in Chinese patients with familial exudative vitreoretinopathy. (PMID:25352738)
• These results suggest that stroma-derived p53 plays a pivotal role in epithelial cancer progression and that TSPAN12 and CXCL6 are potential targets for lung cancer therapy. (PMID:25512506)
• Among the patients with pathogenic mutations detected, FZD4 mutations accounted for the largest proportion of autosomal inheritance FEVR cases (13/18 patients, 72.2%), followed by LRP5 (4/18 patients, 22.2%) and TSPAN12 (1/18 patients, 5.6%). (PMID:26244290)
• The authors report a case of familial exudative vitreoretinopathy in the spectrum of osteoporosis pseudoglioma syndrome associated with novel mutations of the LRP5 and TSPAN12 genes that resulted in a phenotype similar to bilateral persistent fetal vasculature. (PMID:27007396)
• Several novel mutations (missense, non-stop and insertion) were detected in the coding regions of FZD4, TSPAN12 and ZNF408 genes among the unrelated vitreoretinopathy probands.The mutations in FZD4 and TSPAN12 were involved in autosomal dominant and autosomal recessive families and further validates the involvement of these gene in familial exudative vitreoretinopathy development. (PMID:27316669)
• FEVR-associated genes contributing to the disorder’s autosomal dominant inheritance pattern in Korea, we determined that patients with TSPAN12 large deletions were more common than patients with single nucleotide variants in TSPAN12. (PMID:28002565)
• The novel variant p.Cys189Arg in TSPAN12 was not identified in the affected 14-year-old daughter. Thus, we conclude that the heterozygous FZD4 missense variant c.349T>C most likely represents a causative dominant mutation in this family with FEVR. (PMID:28211206)
• TSPAN12 promotes chemoresistance and proliferation of small cell lung carcinoma under the regulation of miR-495. (PMID:28302484)
• Among the detected mutations, LRP5 accounted for the largest proportion with a mean mutation rate of 16.1% (5/31, 16.1%), followed by NDP (3/31, 9.7%), FZD4 (2/31, 6.5%), TSPAN12 (1/31, 3.2%), and KIF11 (1/31, 3.2%). All the novel changes were predicted to be pathogenic by a series of bioinformatics analyses. (PMID:28494495)
• We identified two novel heterozygous deletion mutations [LRP5, c.4053 DelC (p.Ile1351IlefsX88); TSPAN12, EX8Del] using targeted NGS as a causative mutation for Familial exudative vitreoretinopathy (FEVR). (PMID:28867931)
• The screening of candidate genes namely NDP, FZD4 and TSPAN12 led to the identification of six major coding region variants in 36 ROP probands. (PMID:28982955)
• Probands with LRP5 or NDP mutations were mainly categorized into group III and IV, TSPAN12 mutations were mainly observed in probands with group IV and V FEVR. (PMID:29181528)
• This is the first study to report a group of patients with digenic familial exudative vitreoretinopathy (FEVR). In most affected eyes, the stage was more severe than stage 3. We speculate that the phenotype of FEVR is more severe in patients with digenic rather than monogenic variants of FEVR-related genes. (PMID:30097784)
• Our data indicate FEVR status is associated with a significantly smaller FAZ, decreased vascular density in the fovea. In addition, patients with the LRP5 mutation had a milder phenotype than those with the FDZ4 or TSPAN12 mutations. (PMID:30513533)
• tetraspanin 7 cytoplasmic ends has epitopes that are recognized by autoantibodies in type 1 diabetes (PMID:30789994)
• Genetic variants of TSPAN12 gene in patients with retinopathy of prematurity. (PMID:31009104)
• The positive rate for pathogenic mutations in the known FEVR-associated genes was 38.9% (21/54). Among the mutations, LRP5 mutation was the predominant, accounting for 66.7% (14/21) of genetic positive patients. Patients with FEVR-RRD due to LRP5 mutations have less retinal vascular leakage or neovasculization than do patients with FEVR-RRD due to TSPAN12/FZD4 mutations. (PMID:31237656)
• TSPAN12 could be a novel molecular target for the treatment of ovarian cancer. (PMID:31362470)
• Four novel heterozygous TSPAN12 (Tetraspanin 12) mutations, including two single-base substitution mutations and two small-deletion mutations, were identified in four Chinese familial exudative vitreoretinopathy families: c.1A>G (p.0), c.614G>A (p.G205D), c.695delT (p.V232Gfs*7), and c.833_842del (p.L278Qfs*25). (PMID:31513438)
• Heterozygous mutation in TSPAN12 gene is associated with familial exudative vitreoretinopathy. (PMID:31755339)
• Up-regulated miR-196b-5p promotes lung cancer cell migration, proliferation, and cell cycle through directly targeting the tumor suppressors, GATA6 and TSPAN12. (PMID:32041891)
• Pathogenic variants and associated phenotypic spectrum of TSPAN12 based on data from a large cohort. (PMID:33907885)
• Whole-Exome Sequencing Reveals Novel TSPAN12 Variants in Autosomal Dominant Familial Exudative Vitreoretinopathy. (PMID:34077673)
• Novel mutation in TSPAN12 associated with familial exudative vitreoretinopathy in a Chinese pedigree. (PMID:34445920)
• Loss of Endothelial TSPAN12 Promotes Fibrostenotic Eosinophilic Esophagitis via Endothelial Cell-Fibroblast Crosstalk. (PMID:34687736)
• A novel stop codon mutation of TSPAN12 gene in Chinese patients with familial exudative vitreoretinopathy. (PMID:34738848)
• Five novel copy number variations detected in patients with familial exudative vitreoretinopathy. (PMID:34924743)
• Ocular phenotype and genetical analysis in patients with retinopathy of prematurity. (PMID:35022017)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tspan12	ENSDARG00000032389
mus_musculus	Tspan12	ENSMUSG00000029669
rattus_norvegicus	Tspan12	ENSRNOG00000059016

Paralogs (32): TSPAN6 (ENSG00000000003), CD9 (ENSG00000010278), TSPAN9 (ENSG00000011105), TSPAN17 (ENSG00000048140), TSPAN32 (ENSG00000064201), CD82 (ENSG00000085117), TSPAN15 (ENSG00000099282), CD37 (ENSG00000104894), UPK1A (ENSG00000105668), TSPAN13 (ENSG00000106537), TSPAN14 (ENSG00000108219), CD81 (ENSG00000110651), TSPAN11 (ENSG00000110900), PRPH2 (ENSG00000112619), UPK1B (ENSG00000114638), TSPAN1 (ENSG00000117472), TSPAN8 (ENSG00000127324), TSPAN16 (ENSG00000130167), TSPAN2 (ENSG00000134198), CD63 (ENSG00000135404), TSPAN31 (ENSG00000135452), TSPAN3 (ENSG00000140391), CD53 (ENSG00000143119), ROM1 (ENSG00000149489), TSPAN7 (ENSG00000156298), TSPAN18 (ENSG00000157570), TSPAN33 (ENSG00000158457), TSPAN5 (ENSG00000168785), CD151 (ENSG00000177697), TSPAN10 (ENSG00000182612), TSPAN4 (ENSG00000214063), TSPAN19 (ENSG00000231738)

Protein

Protein identifiers

Tetraspanin-12 — O95859 (reviewed: O95859)

Alternative names: Tetraspan NET-2, Transmembrane 4 superfamily member 12

All UniProt accessions (6): O95859, C9IZ82, C9J9U1, C9JC05, C9JQM0, H7C0X9

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of cell surface receptor signal transduction. Plays a central role in retinal vascularization by regulating norrin (NDP) signal transduction. Acts in concert with norrin (NDP) to promote FZD4 multimerization and subsequent activation of FZD4, leading to promote accumulation of beta-catenin (CTNNB1) and stimulate LEF/TCF-mediated transcriptional programs. Suprisingly, it only activates the norrin (NDP)-dependent activation of FZD4, while it does not activate the Wnt-dependent activation of FZD4, suggesting the existence of a Wnt-independent signaling that also promote accumulation the beta-catenin (CTNNB1). Acts as a regulator of membrane proteinases such as ADAM10 and MMP14/MT1-MMP. Activates ADAM10-dependent cleavage activity of amyloid precursor protein (APP). Activates MMP14/MT1-MMP-dependent cleavage activity.

Subunit / interactions. Component of a complex, at least composed of TSPAN12, FZD4 and norrin (NDP). Interacts (when palmitoylated) with ADAM10. Interacts with MMP14/MT1-MMP.

Subcellular location. Cell membrane.

Post-translational modifications. Palmitoylated; required for interaction with ADAM10. The precise position of palmitoylated residues is unclear and occurs either on Cys-9, Cys-12 and/or Cys-83.

Disease relevance. Vitreoretinopathy, exudative 5 (EVR5) [MIM:613310] An autosomal dominant form of exudative vitreoretinopathy, a disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. The disease is caused by variants affecting the gene represented in this entry. TSPAN12 dominant and recessive mutations have been identified in patients with exudative vitreoretinopathy. Patients with mutations in both alleles of TSPAN12 have severe exudative vitreoretinopathy or retinal dysplasia. These mutations appear to result in a milder phenotype in heterozygous mutation carriers.

Similarity. Belongs to the tetraspanin (TM4SF) family.

Isoforms (2)

UniProt ID	Names	Canonical?
O95859-1	1	yes
O95859-2	2

RefSeq proteins (1): NP_036470* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000301	Tetraspanin_animals	Family
IPR008952	Tetraspanin_EC2_sf	Homologous_superfamily
IPR018499	Tetraspanin/Peripherin	Family
IPR018503	Tetraspanin_CS	Conserved_site

Pfam: PF00335

UniProt features (25 total): sequence variant 8, topological domain 5, transmembrane region 4, lipid moiety-binding region 3, mutagenesis site 3, chain 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9MAN	ELECTRON MICROSCOPY	3.78

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95859-F1	80.41	0.47

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 (3): 9, 12, 83

Mutagenesis-validated functional residues (3):

Position	Phenotype
9	impairs interaction with adam10; when associated with s-12 and s-83.
12	impairs interaction with adam10; when associated with s-9 and s-83.
83	impairs interaction with adam10; when associated with s-9 and s-12.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 227 (showing top): ACTACCT_MIR196A_MIR196B, TGACCTY_ERR1_Q2, GOBP_NEURAL_RETINA_DEVELOPMENT, TANG_SENESCENCE_TP53_TARGETS_UP, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GATA6_01, GOBP_BLOOD_VESSEL_MORPHOGENESIS, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOBP_RETINA_LAYER_FORMATION, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GATA1_02, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOBP_SENSORY_ORGAN_MORPHOGENESIS, CUI_TCF21_TARGETS_2_DN

GO Biological Process (6): angiogenesis (GO:0001525), cell surface receptor signaling pathway (GO:0007166), retina layer formation (GO:0010842), maintenance of blood-brain barrier (GO:0035633), regulation of angiogenesis (GO:0045765), Norrin signaling pathway (GO:0110135)

GO Molecular Function (1): protein binding (GO:0005515)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure formation involved in morphogenesis	2
blood vessel morphogenesis	1
signal transduction	1
neural retina development	1
retina morphogenesis in camera-type eye	1
tissue homeostasis	1
angiogenesis	1
regulation of anatomical structure morphogenesis	1
regulation of vasculature development	1
cell surface receptor signaling pathway	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

590 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TSPAN12	NDP	Q00604	997
TSPAN12	FZD4	Q9ULV1	997
TSPAN12	LRP5	O75197	986
TSPAN12	ZNF408	Q9H9D4	841
TSPAN12	ADGRA2	Q96PE1	680
TSPAN12	TSPAN15	O95858	615
TSPAN12	ADAM10	O14672	610
TSPAN12	KIF11	P52732	604
TSPAN12	ZFPM1	Q8IX07	590
TSPAN12	LRP6	O75581	564
TSPAN12	WNT3A	P56704	529
TSPAN12	RECK	O95980	506
TSPAN12	TSPAN17	Q96FV3	493
TSPAN12	WNT7A	O00755	476
TSPAN12	RCBTB1	Q8NDN9	469

IntAct

72 interactions, top by confidence:

A	B	Type	Score
TFCP2	TSPAN12	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	TSPAN12	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	TSPAN12	psi-mi:“MI:0915”(physical association)	0.560
EMP3	TSPAN12	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	RNF152	psi-mi:“MI:0915”(physical association)	0.560
CDS2	TSPAN12	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	PMP22	psi-mi:“MI:0915”(physical association)	0.560
MGST3	TSPAN12	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	IGFBP5	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	MARCHF2	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	TMEM147	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	NINJ2	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	TMEM182	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	STX8	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	CTXN3	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	EMP3	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	TMEM140	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	CYBC1	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	TEX264	psi-mi:“MI:0915”(physical association)	0.560
GPR37L1	TSPAN12	psi-mi:“MI:0915”(physical association)	0.560
GPR25	TSPAN12	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	RFT1	psi-mi:“MI:0915”(physical association)	0.560
CXCL16	TSPAN12	psi-mi:“MI:0915”(physical association)	0.560
TSPAN12	ADAM10	psi-mi:“MI:0914”(association)	0.500

BioGRID (24): TSPAN12 (Two-hybrid), TSPAN12 (Two-hybrid), TSPAN12 (Two-hybrid), TSPAN12 (Two-hybrid), PMP22 (Two-hybrid), IGFBP5 (Two-hybrid), EMP3 (Two-hybrid), MGST3 (Two-hybrid), TMEM140 (Two-hybrid), TMEM218 (Two-hybrid), CXCL16 (Two-hybrid), RFT1 (Two-hybrid), TEX264 (Two-hybrid), GPR37L1 (Two-hybrid), GPR25 (Two-hybrid)

ESM2 similar proteins: A0JPH4, A4IIV4, A6NGA9, A8MUP6, D3Z7H4, D3ZK93, O42282, O60478, O75204, O95859, P0DP42, P38551, P58418, Q08CE6, Q0II41, Q11085, Q29RH7, Q2KHT4, Q2M2E3, Q32KQ5, Q32LT7, Q3SZT1, Q4V922, Q504G0, Q569A2, Q5CZV0, Q5FWC3, Q5M962, Q5R8B5, Q5RCD5, Q5VW38, Q5XGU1, Q5ZIF5, Q6AXT9, Q6AYL2, Q6GV27, Q6GV28, Q6UXU4, Q7TQI0, Q8BGP5

Diamond homologs: A0A8V0ZLT4, A1L157, B0BM39, B3VSC2, O35566, O60636, O70352, O75954, O95859, O97703, P19075, P21926, P30409, P30932, P31053, P35762, P40237, P40239, P40240, P40241, P48509, P60033, P60034, P61170, P61171, P62079, P62080, Q06AA5, Q17QJ5, Q3ZCD0, Q4V8E0, Q58CY8, Q58DN3, Q5R8B5, Q5R9S6, Q5RH71, Q61470, Q62745, Q68VK5, Q6DCQ3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TSPAN12	up-regulates	NDP

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	39
Likely pathogenic	9
Uncertain significance	148
Likely benign	67
Benign	28

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1026378	NM_012338.4(TSPAN12):c.614G>A (p.Gly205Asp)	Pathogenic
1068154	NM_012338.4(TSPAN12):c.641_642insTTTTTTTTTTNNNNNNNNNNATTACAGGCGTGAGCCACCGCGCCCGGCCAATGTATTCCTTTTT (p.Leu214fs)	Pathogenic
1071716	NC_000007.13:g.(?120428646)(120446746_?)del	Pathogenic
1071783	NM_012338.4(TSPAN12):c.547del (p.Val183fs)	Pathogenic
1075851	NM_012338.4(TSPAN12):c.2T>A (p.Met1Lys)	Pathogenic
1172699	NM_012338.4(TSPAN12):c.301dup (p.Leu101fs)	Pathogenic
126504	NM_012338.4(TSPAN12):c.67-1G>C	Pathogenic
126506	NM_012338.4(TSPAN12):c.285+1G>A	Pathogenic
1334684	NM_012338.4(TSPAN12):c.176_179del (p.Tyr59fs)	Pathogenic
1370740	NM_012338.4(TSPAN12):c.581del (p.His194fs)	Pathogenic
1403438	NM_012338.4(TSPAN12):c.434G>A (p.Trp145Ter)	Pathogenic
1457167	NM_012338.4(TSPAN12):c.543C>A (p.Cys181Ter)	Pathogenic
1489431	NM_012338.4(TSPAN12):c.361-2A>G	Pathogenic
1687582	NM_012338.4(TSPAN12):c.345T>G (p.Tyr115Ter)	Pathogenic
2027545	NM_012338.4(TSPAN12):c.396del (p.Ala133fs)	Pathogenic
2028147	NM_012338.4(TSPAN12):c.67-2A>C	Pathogenic
2034313	NM_012338.4(TSPAN12):c.101G>A (p.Trp34Ter)	Pathogenic
236067	NM_012338.4(TSPAN12):c.542G>T (p.Cys181Phe)	Pathogenic
2418951	NM_012338.4(TSPAN12):c.375G>A (p.Trp125Ter)	Pathogenic
2425799	NC_000007.13:g.(?120478811)(120478986_?)del	Pathogenic
2425800	NC_000007.13:g.(?120428646)(120446766_?)del	Pathogenic
2836747	NM_012338.4(TSPAN12):c.295del (p.Ser99fs)	Pathogenic
2837890	NM_012338.4(TSPAN12):c.469-1G>C	Pathogenic
2866662	NM_012338.4(TSPAN12):c.214del (p.Cys72fs)	Pathogenic
319	NM_012338.4(TSPAN12):c.709G>C (p.Ala237Pro)	Pathogenic
321	NM_012338.4(TSPAN12):c.212_218dup (p.Phe73fs)	Pathogenic
322	NM_012338.4(TSPAN12):c.419T>A (p.Leu140Ter)	Pathogenic
323	NM_012338.4(TSPAN12):c.361-5_361-1del	Pathogenic
3245905	NC_000007.13:g.(?120446640)(120533198_?)del	Pathogenic
3248817	NM_012338.4(TSPAN12):c.94del (p.Ser32fs)	Pathogenic

SpliceAI

2152 predictions. Top by Δscore:

Variant	Effect	Δscore
7:120788893:CAACC:C	acceptor_gain	1.0000
7:120806543:CCTCA:C	donor_loss	1.0000
7:120806544:CTCAC:C	donor_loss	1.0000
7:120806545:TCACC:T	donor_loss	1.0000
7:120806546:CACC:C	donor_loss	1.0000
7:120806547:A:AG	donor_loss	1.0000
7:120806548:C:A	donor_loss	1.0000
7:120806548:CCT:C	donor_gain	1.0000
7:120806574:T:TA	donor_gain	1.0000
7:120806693:C:CC	acceptor_gain	1.0000
7:120838908:CTACC:C	acceptor_gain	1.0000
7:120838911:CC:C	acceptor_gain	1.0000
7:120838912:CC:C	acceptor_gain	1.0000
7:120840110:C:CC	acceptor_gain	1.0000
7:120855305:AATTT:A	donor_gain	1.0000
7:120856692:A:AC	donor_gain	1.0000
7:120856693:C:CC	donor_gain	1.0000
7:120856693:CTTA:C	donor_gain	1.0000
7:120856694:TTA:T	donor_loss	1.0000
7:120856695:TA:T	donor_loss	1.0000
7:120856696:A:AC	donor_gain	1.0000
7:120856696:AC:A	donor_gain	1.0000
7:120856697:C:CC	donor_gain	1.0000
7:120856697:CC:C	donor_gain	1.0000
7:120856830:CGAT:C	acceptor_gain	1.0000
7:120856844:C:CT	acceptor_gain	1.0000
7:120856845:G:T	acceptor_gain	1.0000
7:120857813:CACTT:C	donor_loss	1.0000
7:120857814:ACTTA:A	donor_loss	1.0000
7:120857815:CTTA:C	donor_loss	1.0000

AlphaMissense

2007 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:120806657:C:A	W168C	1.000
7:120806657:C:G	W168C	1.000
7:120806659:A:G	W168R	1.000
7:120806659:A:T	W168R	1.000
7:120806679:C:T	G161E	1.000
7:120806686:A:G	C159R	1.000
7:120788818:C:T	G231E	0.999
7:120788819:C:G	G231R	0.999
7:120788819:C:T	G231R	0.999
7:120788892:A:C	C206W	0.999
7:120788893:C:G	C206S	0.999
7:120788893:C:T	C206Y	0.999
7:120788894:A:G	C206R	0.999
7:120788894:A:T	C206S	0.999
7:120806595:C:G	C189S	0.999
7:120806596:A:G	C189R	0.999
7:120806596:A:T	C189S	0.999
7:120806616:C:G	C182S	0.999
7:120806616:C:T	C182Y	0.999
7:120806617:A:T	C182S	0.999
7:120806618:G:C	C181W	0.999
7:120806619:C:A	C181F	0.999
7:120806619:C:G	C181S	0.999
7:120806619:C:T	C181Y	0.999
7:120806620:A:G	C181R	0.999
7:120806620:A:T	C181S	0.999
7:120806658:C:G	W168S	0.999
7:120806661:T:A	D167V	0.999
7:120806661:T:G	D167A	0.999
7:120806662:C:A	D167Y	0.999

dbSNP variants (sampled 300 via entrez): RS1000003142 (7:120857581 C>T), RS1000004431 (7:120790258 G>A), RS1000119894 (7:120790548 T>C,G), RS1000191413 (7:120817106 G>A), RS1000200015 (7:120857717 C>A,T), RS1000250113 (7:120835115 T>G), RS1000275486 (7:120814234 T>C), RS1000412752 (7:120816850 T>C), RS1000429248 (7:120853974 C>T), RS1000483012 (7:120854347 C>G), RS1000518485 (7:120821045 AAATGAATGAAG>A), RS1000518956 (7:120800303 G>A,T), RS1000549646 (7:120847578 T>C), RS1000550121 (7:120800639 T>C), RS1000619486 (7:120858542 C>A,T)

Disease associations

OMIM: gene MIM:613138 | disease phenotypes: MIM:613310, MIM:221900, MIM:310600, MIM:133780

GenCC curated gene-disease

Disease	Classification	Inheritance
exudative vitreoretinopathy 5	Definitive	Autosomal dominant
exudative vitreoretinopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
TSPAN12-related exudative vitreoretinopathy	Definitive	SD

Mondo (8): exudative vitreoretinopathy 5 (MONDO:0013218), retinal disorder (MONDO:0005283), inherited retinal dystrophy (MONDO:0019118), persistent hyperplastic primary vitreous, autosomal recessive (MONDO:0009097), Norrie disease (MONDO:0010691), exudative vitreoretinopathy (MONDO:0019516), optic atrophy (MONDO:0003608), vitreoretinal degeneration (MONDO:0020248)

Orphanet (6): Familial exudative vitreoretinopathy (Orphanet:891), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Norrie disease (Orphanet:649), Persistent hyperplastic primary vitreous (Orphanet:91495), OBSOLETE: Congenital blindness due to retinal non-attachment (Orphanet:300337), OBSOLETE: Vitreoretinal degeneration (Orphanet:98670)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000533	Chorioretinal atrophy
HP:0000568	Microphthalmia
HP:0000594	Shallow anterior chamber
HP:0000618	Blindness
HP:0001004	Lymphedema
HP:0001141	Severely reduced visual acuity
HP:0001147	Retinal exudate
HP:0001256	Mild intellectual disability
HP:0001270	Motor delay
HP:0001493	Falciform retinal fold
HP:0004349	Reduced bone mineral density
HP:0007663	Reduced visual acuity
HP:0007685	Avascular peripheral retina
HP:0007773	Vitreoretinopathy
HP:0007902	Vitreous hemorrhage
HP:0007917	Tractional retinal detachment
HP:0011342	Mild global developmental delay
HP:0012230	Rhegmatogenous retinal detachment
HP:0012795	Abnormal optic disc morphology
HP:0030490	Exudative vitreoretinopathy
HP:0030496	Macular exudate
HP:0030503	Macular telangiectasia
HP:0030666	Retinal neovascularization
HP:0031526	Subretinal fluid
HP:0040049	Macular edema

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006979_150	Heel bone mineral density	3.000000e-12
GCST008522_96	Bitter alcoholic beverage consumption	9.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0010092	bitter alcoholic beverage consumption measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
C567648	Exudative Vitreoretinopathy 5 (supp.)
C537849	Norrie disease (supp.)
C566966	Persistent Hyperplastic Primary Vitreous, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, increases methylation	3
Estradiol	affects cotreatment, decreases expression	3
trichostatin A	affects cotreatment, decreases expression	2
Resveratrol	affects cotreatment, decreases expression	2
Cisplatin	decreases expression, affects response to substance	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	affects expression, decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
chloroacetaldehyde	decreases expression	1
arsenite	decreases methylation	1
o,p’-DDT	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	increases expression	1
pentanal	increases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
jinfukang	decreases expression	1
Cidofovir	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Camptothecin	increases expression	1
Copper	affects cotreatment, decreases expression	1
Dactinomycin	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06520410	PHASE4	RECRUITING	Safety and Efficacy of 18 mm Short Vitrectomy Probe for Pediatric Vitreoretinal Surgeries
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT05107921	PHASE2	UNKNOWN	Bromfenac Sodium Hydrate Eye Drops in Familial Exudative Vitreoretinopathy
NCT01373476	PHASE2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	PHASE2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT01064505	PHASE1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	PHASE1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION
NCT00106756	Not specified	COMPLETED	Clinical and Genetic Studies of Familial Exudative Vitreoretinopathy
NCT04311112	PHASE2/PHASE3	WITHDRAWN	Safety and Efficacy of Zuretinol Acetate in Subjects With Inherited Retinal Disease
NCT04008121	EARLY_PHASE1	RECRUITING	Feasibility and Safety of MB-102 in Ocular Angiography as Compared to Fluorescein Sodium
NCT00259701	Not specified	COMPLETED	Microvascular Reactivity.
NCT00331370	Not specified	UNKNOWN	Hypertension Related Damage to the Microcirculation in South Asian: Emergence, Predictive Power and Reversibility
NCT00618644	Not specified	WITHDRAWN	Ranibizumab for Neovascularization in Sickle Cell Retinopathy
NCT00735657	Not specified	COMPLETED	Anesthesia for Pars Plana Vitrectomy (PPV) With Insulin Needle
NCT00828425	Not specified	COMPLETED	Management of Diabetes Mellitus Patients With Retinopathy
NCT00969956	Not specified	TERMINATED	Time To Complications Occurs in Diabetes
NCT01412905	Not specified	COMPLETED	Telemedicine Retinal Screening Utilizing a Mobile Medical Unit
NCT01546766	Not specified	COMPLETED	Rapid, Non-invasive, Regional Functional Imaging of the Retina. (Diabetic Retinopathy Diagnosis Device)
NCT01552993	Not specified	TERMINATED	Registration and Treatment of Pain During Eye Examination of Prematurity
NCT01815567	Not specified	COMPLETED	DETECT and Retinal Outcomes in Hypertension
NCT02321904	Not specified	COMPLETED	Corneal Confocal Microscopy to Detect Diabetic Neuropathy in Children
NCT02466607	Not specified	COMPLETED	Study of Stimulus Parameters in Flicker Electroretinogram (ERG)
NCT02558478	Not specified	UNKNOWN	Identification of New Genes Implicated in Rare Neurosensory Diseases by Whole Exome Sequencing
NCT02702973	Not specified	UNKNOWN	Characteristic Analysis of Retinopathy Associated With High Doses of Interferon α-2b Therapy
NCT03011541	Not specified	RECRUITING	Stem Cell Ophthalmology Treatment Study II
NCT03542734	Not specified	RECRUITING	Cognitive Impairment, Retinopathy, and Cerebrovascular Lesions in the Elderly
NCT03901898	Not specified	COMPLETED	Feasibility of an Intervention to Increase Diabetic Retinopathy Screening Attendance
NCT04819893	Not specified	RECRUITING	Study of the Involvement of Fatty Acids in Retinopathy of Prematurity: Relationship Between Retinopathy of Prematurity and the Rate of Expression of Transplacental Fatty Acid Receptors.
NCT05921981	Not specified	COMPLETED	Multisensory Stimulation Versus White Noise
NCT06239064	Not specified	ACTIVE_NOT_RECRUITING	Early Genetic Identification of Obesity
NCT06355219	Not specified	COMPLETED	Macrovascular and Microvascular Morbidity and Mortality After Metabolic Surgery Versus Medicines
NCT06837181	Not specified	RECRUITING	Studying the Presence of CFRD Complications With Thoughtful Recruitment (SPeCTRuM)