SEMA3E

Summary

SEMA3E (semaphorin 3E, HGNC:10727) is a protein-coding gene on chromosome 7q21.11, encoding Semaphorin-3E (O15041). Plays an important role in signaling via the cell surface receptor PLXND1.

Semaphorins are a large family of conserved secreted and membrane associated proteins which possess a semaphorin (Sema) domain and a PSI domain (found in plexins, semaphorins and integrins) in the N-terminal extracellular portion. Based on sequence and structural similarities, semaphorins are put into eight classes: invertebrates contain classes 1 and 2, viruses have class V, and vertebrates contain classes 3-7. Semaphorins serve as axon guidance ligands via multimeric receptor complexes, some (if not all) containing plexin proteins. This gene encodes a class 4 semaphorin. This gene encodes a class 3 semaphorin. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 9723 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CHD7-related CHARGE syndrome (Moderate, GenCC) — +3 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 918 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 103
• MANE Select transcript: NM_012431

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10727
Approved symbol	SEMA3E
Name	semaphorin 3E
Location	7q21.11
Locus type	gene with protein product
Status	Approved
Aliases	M-SemaK, KIAA0331, coll-5
Ensembl gene	ENSG00000170381
Ensembl biotype	protein_coding
OMIM	608166
Entrez	9723

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding_CDS_not_defined, 3 protein_coding, 1 nonsense_mediated_decay

ENST00000442159, ENST00000453333, ENST00000642232, ENST00000643230, ENST00000643441, ENST00000644381, ENST00000891111

RefSeq mRNA: 2 — MANE Select: NM_012431 NM_001178129, NM_012431

CCDS: CCDS34674

Canonical transcript exons

ENST00000643230 — 17 exons

Exon	Start	End
ENSE00001128969	83385294	83385433
ENSE00001128977	83386983	83387050
ENSE00001128985	83392555	83392721
ENSE00001128996	83394297	83394338
ENSE00001129005	83396638	83396729
ENSE00001129012	83400028	83400250
ENSE00001129017	83402632	83402776
ENSE00001129025	83405450	83405519
ENSE00001129033	83405945	83406059
ENSE00001129040	83407097	83407239
ENSE00001129061	83418390	83418483
ENSE00001129071	83466482	83466601
ENSE00001129078	83469243	83469302
ENSE00003627918	83490114	83490274
ENSE00003785718	83408368	83408487
ENSE00003826107	83648428	83649139
ENSE00003830609	83363238	83368038

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 88.30.

FANTOM5 (CAGE): breadth broad, TPM avg 3.2571 / max 183.6298, expressed in 642 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84639	1.0275	400
84635	0.7822	254
84636	0.7387	333
84637	0.2522	119
84633	0.1771	97
84638	0.1557	76
84634	0.1238	74

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	88.30	gold quality
calcaneal tendon	UBERON:0003701	87.81	gold quality
blood vessel layer	UBERON:0004797	84.89	gold quality
colonic epithelium	UBERON:0000397	78.61	gold quality
tendon	UBERON:0000043	76.64	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.24	gold quality
islet of Langerhans	UBERON:0000006	75.78	gold quality
gall bladder	UBERON:0002110	75.47	gold quality
mucosa of stomach	UBERON:0001199	75.28	gold quality
buccal mucosa cell	CL:0002336	74.69	gold quality
layer of synovial tissue	UBERON:0007616	74.64	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	73.74	gold quality
lower esophagus muscularis layer	UBERON:0035833	72.90	gold quality
lower esophagus	UBERON:0013473	72.79	gold quality
urinary bladder	UBERON:0001255	71.35	gold quality
synovial joint	UBERON:0002217	71.27	gold quality
cartilage tissue	UBERON:0002418	71.14	gold quality
rectum	UBERON:0001052	69.02	gold quality
muscle layer of sigmoid colon	UBERON:0035805	68.30	gold quality
prefrontal cortex	UBERON:0000451	68.03	gold quality
endometrium epithelium	UBERON:0004811	67.06	gold quality
lateral nuclear group of thalamus	UBERON:0002736	66.96	gold quality
endothelial cell	CL:0000115	66.38	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	65.96	gold quality
substantia nigra pars reticulata	UBERON:0001966	65.50	gold quality
ventricular zone	UBERON:0003053	65.08	gold quality
ganglionic eminence	UBERON:0004023	64.86	gold quality
smooth muscle tissue	UBERON:0001135	64.60	gold quality
substantia nigra	UBERON:0002038	64.44	gold quality
substantia nigra pars compacta	UBERON:0001965	63.91	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-23	yes	5801.31
E-ENAD-27	yes	417.96
E-GEOD-83139	yes	315.60
E-MTAB-5061	yes	17.64
E-GEOD-81608	yes	10.33
E-ANND-3	yes	8.54
E-HCAD-31	no	2.63

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

159 targeting SEMA3E, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 32)

• The translocation envolving chromosomes 2 and 7 with SEMA3E within 200 kb of the translocation breakpoint on 7q21.11 in a patient with CHARGE syndrome. (PMID:15235037)
• Sema3E inhibits tumor progression from MDA-231 but not MDA-435 cells. It inhibits tumors angiogenesis, but less effectively then other tested class-3 semaphorins. Tumor inhibition might be as a result of the expression levels of PlexD1 on the tumor cells. (PMID:18818766)
• These results show that PLXND1 expression during tumor development is strongly correlated with both invasive behavior and metastasis, but exclude Sema3E as an activating ligand. (PMID:18974298)
• Sema3E-Plexin D1 signaling in cancer cells is crucially implicated in their metastatic behavior and may therefore be a promising target for strategies aimed at blocking tumor metastasis. (PMID:20664171)
• Semaphorin 3E is aberrantly expressed in prostate cancer and affects cell adhesion and motility, indicating a role in the Sems3E/PlexinD1 signaling pathway. (PMID:20949546)
• Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice (PMID:21505259)
• SEMA3E is a target gene of the BACH1 transcription factor according to ChIP-seq analysis in HEK 293 cells. (PMID:21555518)
• analysis of Sema3E/plexin-D1 mediated epithelial-to-mesenchymal transition in ovarian endometrioid cancer (PMID:21559368)
• a novel phospholipid-regulated antiangiogenic signaling pathway whereby Sema3E activates Arf6 through Plexin-D1 and consequently controls integrin-mediated endothelial cell attachment to the extracellular matrix and migration. (PMID:21795701)
• Furin-resistant Sema3E inhibits endothelial cells and hampers tumour angiogenesis and tumour growth. (PMID:22247010)
• Loss of Sema3E expression is associated with biochemical recurrence of patients with low- and intermediate-risk prostate cancer. (PMID:23906303)
• Semaphorin 3E inhibits human airway smooth muscle cell proliferation and migration. (PMID:23932461)
• A critical role of Sema3E/Plexin D1 interaction in tumor resistance to apoptosis. (PMID:24139859)
• Semaphorin 3d requires neuropilin 1 or PI3K/Akt, whereas semaphorin 3e requires plexin D1 in directing endothelial motility. (PMID:24825896)
• The identification and characterization of SH3BP1 as a novel downstream effector of Sema3E-PlexinD1 provides an explanation for how extracellular signals are translated into cytoskeletal changes and unique cell behavior. (PMID:24841563)
• The ANGPTL4 may be a candidate target in DME treatment and a biomarker of ischemic-induced retinopathy, including diabetic retinopathy. (PMID:25687026)
• these results identify SEMA3E as an essential gene for GnRH neuron development, uncover a neurotrophic function for SEMA3E in the developing brain (PMID:25985275)
• Authors suggest that silencing of Sema3E contributes to the pathogenesis of gastric cancer. (PMID:26036259)
• Infantile hemangioma-derived stem cells and endothelial cells are inhibited by SEMA3E and SEMA3F. (PMID:26086095)
• Findings suggest that Plexin-D1/class III semaphorin (Sema3E) axis is triggered in systemic sclerosis (SSc) endothelium. (PMID:26292963)
• suggested that miR-4282 is a tumor suppressor in colorectal carcinoma cells and exerted its inhibitory effect on the tumor cells through targeting Sema3E by inhibiting Sema3E translation or enhancing Sema3E mRNA degradation (PMID:27120047)
• Results show high expression level of SEMA3E which correlated with lymph node involvement, metastatic progression and a significant association with poor prognosis in gastric cancer patients. Also, in vitro studies reveal that SEMA3E caused cell proliferation and anchorage-independent cell growth in the intestinal type of gastric cancer. (PMID:27572291)
• This study suggests that NRP1 expression and LVD are independent factors that are likely to predict the risk of LN metastasis in squamous cell carcinoma (SCC)of the tongue, whereas the expression of VEGFC, VEGFR3, CCR7, and SEMA3E are nonindependent predictive factors (PMID:27666723)
• Sema3E induced cell proliferation via acting through the MAPK/ERK pathway. (PMID:27911862)
• Sema3E could be considered an essential regulatory mediator involved in modulation of neutrophil migration throughout the course of neutrophilic inflammation. (PMID:27913633)
• This study aims to investigate whether the Tribbles 3 Q84R polymorphism has profound effects on serum semaphorin 3E and what effect semaphorin 3E exerts on carotid atherosclerosis. (PMID:28249916)
• Collectively, our data demonstrate that Sema3E expression is decreased in severe allergic asthma, suggestive of a potential role of this molecule in regulating asthmatic phenotype. (PMID:28506853)
• recently discovered regulatory role of semaphorin3E in modulating immune cells and structural cells function in the airways. These findings support the concept of semaphorin3E/plexinD1 axis as a therapeutic target in allergic asthma. (PMID:30447428)
• The SEMA3E is reduced in colitis and modulates colonic inflammation by regulating the interaction between CD11c(+) and CD4(+) CD25(-) T-cells via an NF-kappaB-dependent mechanism. (PMID:30736100)
• SEMA3E is a novel regulator in intestinal inflammation that regulates intestinal epithelium apoptosis. (PMID:31170375)
• PLXND1/SEMA3E Promotes Epithelial-Mesenchymal Transition Partly via the PI3K/AKT-Signaling Pathway and Induces Heterogenity in Colorectal Cancer. (PMID:35917012)
• The Combination of Natural Molecules Naringenin, Hesperetin, Curcumin, Polydatin and Quercetin Synergistically Decreases SEMA3E Expression Levels and DPPIV Activity in In Vitro Models of Insulin Resistance. (PMID:37175783)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sema3e	ENSDARG00000036571
mus_musculus	Sema3e	ENSMUSG00000063531
rattus_norvegicus	Sema3e	ENSRNOG00000006631

Paralogs (19): SEMA3F (ENSG00000001617), SEMA3G (ENSG00000010319), SEMA3B (ENSG00000012171), SEMA3A (ENSG00000075213), SEMA3C (ENSG00000075223), SEMA5B (ENSG00000082684), SEMA6A (ENSG00000092421), SEMA4G (ENSG00000095539), SEMA5A (ENSG00000112902), SEMA4F (ENSG00000135622), SEMA6D (ENSG00000137872), SEMA7A (ENSG00000138623), SEMA6C (ENSG00000143434), SEMA3D (ENSG00000153993), SEMA6B (ENSG00000167680), SEMA4C (ENSG00000168758), SEMA4B (ENSG00000185033), SEMA4D (ENSG00000187764), SEMA4A (ENSG00000196189)

Protein

Protein identifiers

Semaphorin-3E — O15041 (reviewed: O15041)

All UniProt accessions (3): O15041, A0A2R8YCX5, F8WCZ5

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in signaling via the cell surface receptor PLXND1. Mediates reorganization of the actin cytoskeleton, leading to the retraction of cell projections. Promotes focal adhesion disassembly and inhibits adhesion of endothelial cells to the extracellular matrix. Regulates angiogenesis, both during embryogenesis and after birth. Can down-regulate sprouting angiogenesis. Required for normal vascular patterning during embryogenesis. Plays an important role in ensuring the specificity of synapse formation.

Subunit / interactions. Interacts with PLXND1.

Subcellular location. Secreted.

Similarity. Belongs to the semaphorin family.

Isoforms (2)

UniProt ID	Names	Canonical?
O15041-1	1	yes
O15041-2	2

RefSeq proteins (2): NP_001171600, NP_036563* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001627	Semap_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR013151	Immunoglobulin_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015513	Semaphorin_3E_Sema	Domain
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016201	PSI	Domain
IPR027231	Semaphorin	Family
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR036352	Semap_dom_sf	Homologous_superfamily

Pfam: PF00047, PF01403

UniProt features (22 total): disulfide bond 6, glycosylation site 5, sequence variant 4, domain 2, signal peptide 1, chain 1, splice variant 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15041-F1	84.62	0.67

Functional residue map

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

Disulfide bonds (6): 105–115, 133–142, 270–382, 294–342, 519–537, 654–729

Glycosylation sites (5): 596, 44, 126, 330, 595

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-416700	Other semaphorin interactions
R-HSA-1266738	Developmental Biology
R-HSA-373755	Semaphorin interactions
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 440 (showing top): GOBP_FOREBRAIN_NEURON_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, REACTOME_OTHER_SEMAPHORIN_INTERACTIONS, GOBP_NEUROGENESIS, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, GOBP_FOREBRAIN_GENERATION_OF_NEURONS, GOBP_NEGATIVE_REGULATION_OF_CELL_SUBSTRATE_ADHESION, GOBP_HYPOTHALAMUS_DEVELOPMENT, GOBP_TAXIS, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_3, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS

GO Biological Process (18): branching involved in blood vessel morphogenesis (GO:0001569), neural crest cell migration (GO:0001755), negative regulation of cell-matrix adhesion (GO:0001953), sprouting angiogenesis (GO:0002040), axon guidance (GO:0007411), regulation of cell shape (GO:0008360), negative regulation of angiogenesis (GO:0016525), gonadotrophin-releasing hormone neuronal migration to the hypothalamus (GO:0021828), positive regulation of cell migration (GO:0030335), negative regulation of neuron apoptotic process (GO:0043524), synapse organization (GO:0050808), negative chemotaxis (GO:0050919), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), semaphorin-plexin signaling pathway (GO:0071526), angiogenesis (GO:0001525), nervous system development (GO:0007399), cell differentiation (GO:0030154), forebrain development (GO:0030900)

GO Molecular Function (5): semaphorin receptor binding (GO:0030215), neuropilin binding (GO:0038191), chemorepellent activity (GO:0045499), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Semaphorin interactions	1
Axon guidance	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
angiogenesis	3
signaling receptor binding	3
blood vessel morphogenesis	2
branching morphogenesis of an epithelial tube	1
neural crest cell development	1
mesenchymal cell migration	1
regulation of cell-matrix adhesion	1
cell-matrix adhesion	1
negative regulation of cell-substrate adhesion	1
axonogenesis	1
neuron projection guidance	1
regulation of cell morphogenesis	1
regulation of biological quality	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
neuron migration	1
hypothalamic tangential migration using cell-axon interactions	1
hypothalamus gonadotrophin-releasing hormone neuron development	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
cell junction organization	1
chemotaxis	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
cell surface receptor signaling pathway	1
anatomical structure formation involved in morphogenesis	1
system development	1
cellular developmental process	1
brain development	1
anatomical structure development	1
receptor ligand activity	1
negative chemotaxis	1
signal transduction	1
signaling receptor activator activity	1
binding	1

Protein interactions and networks

STRING

906 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEMA3E	PLXND1	Q9Y4D7	999
SEMA3E	NRP1	O14786	968
SEMA3E	NRP2	O60462	895
SEMA3E	PLXNA3	P51805	858
SEMA3E	CHD7	Q9P2D1	845
SEMA3E	KDR	P35968	804
SEMA3E	PLXNA1	Q9UIW2	794
SEMA3E	PLXNA4	Q9HCM2	785
SEMA3E	PLXNA2	O75051	755
SEMA3E	PLXNC1	O60486	719
SEMA3E	NETO1	Q8TDF5	600
SEMA3E	PLXNB1	O43157	599
SEMA3E	ROBO2	Q9HCK4	560
SEMA3E	SLIT3	O75094	556
SEMA3E	NTN1	O95631	547

IntAct

7 interactions, top by confidence:

A	B	Type	Score
SEMA3E	PLXND1	psi-mi:“MI:0407”(direct interaction)	0.560
PLXND1	SEMA3E	psi-mi:“MI:0407”(direct interaction)	0.560
	SEMA3E	psi-mi:“MI:0407”(direct interaction)	0.440
SEMA3E	GLDC	psi-mi:“MI:0915”(physical association)	0.400
SEMA3E	CFTR	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (4): SEMA3E (Synthetic Lethality), GLDC (Affinity Capture-MS), SEMA3E (PCA), SEMA3E (Affinity Capture-MS)

ESM2 similar proteins: A0A2D0TC04, A1A4K5, A7E2Z9, A8MWY0, F1QR43, J3SBP3, J3SEZ3, O14638, O15041, O18756, O94923, O95461, P06802, P0DQQ4, P15396, P22413, P79948, P97675, Q13219, Q13822, Q3UZV7, Q5M900, Q5NDE3, Q5NDE4, Q5NDE5, Q5NDE8, Q5R5M5, Q64610, Q66PG1, Q66PG2, Q66PG3, Q6DYE8, Q6FHJ7, Q6GMK0, Q6NRQ1, Q6P9A2, Q8C1F4, Q8JHF2, Q8K1B9, Q8N6G5

Diamond homologs: A7MB70, D3ZTD8, O08665, O09126, O15041, O35464, O42236, O42237, O88632, O95025, O95754, P70275, Q13214, Q13275, Q13591, Q14563, Q17330, Q24322, Q24323, Q26473, Q26972, Q4LFA9, Q5EA85, Q5R7F5, Q5RE75, Q60519, Q62177, Q62178, Q62179, Q62181, Q62217, Q63548, Q64151, Q76KF0, Q8BH34, Q8NFY4, Q90607, Q90663, Q90665, Q92854

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	473
Likely benign	308
Benign	104

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1454415	NC_000007.13:g.(?80276057)(83739925_?)del	Pathogenic
1339484	NM_012431.3(SEMA3E):c.621del (p.Arg208fs)	Likely pathogenic

SpliceAI

3799 predictions. Top by Δscore:

Variant	Effect	Δscore
7:83368038:CCT:C	acceptor_loss	1.0000
7:83368039:CTG:C	acceptor_loss	1.0000
7:83368040:T:G	acceptor_loss	1.0000
7:83385295:T:TA	donor_gain	1.0000
7:83386986:CAAA:C	donor_gain	1.0000
7:83386989:A:AC	donor_gain	1.0000
7:83386990:C:CC	donor_gain	1.0000
7:83387048:CGC:C	acceptor_gain	1.0000
7:83387050:CCT:C	acceptor_loss	1.0000
7:83387051:C:CC	acceptor_gain	1.0000
7:83387051:C:CG	acceptor_loss	1.0000
7:83387052:T:C	acceptor_loss	1.0000
7:83392272:T:A	donor_gain	1.0000
7:83392549:TCTCA:T	donor_loss	1.0000
7:83392550:CTCAC:C	donor_loss	1.0000
7:83392551:TCAC:T	donor_loss	1.0000
7:83392552:CAC:C	donor_loss	1.0000
7:83392554:C:A	donor_loss	1.0000
7:83392717:TGTTG:T	acceptor_gain	1.0000
7:83392718:GTTG:G	acceptor_gain	1.0000
7:83392719:TTG:T	acceptor_gain	1.0000
7:83392720:TG:T	acceptor_gain	1.0000
7:83392722:C:CC	acceptor_gain	1.0000
7:83394291:ACTT:A	donor_loss	1.0000
7:83394292:CTT:C	donor_loss	1.0000
7:83394293:TTACC:T	donor_loss	1.0000
7:83394294:T:TG	donor_loss	1.0000
7:83394295:A:AC	donor_gain	1.0000
7:83394295:A:AG	donor_loss	1.0000
7:83394296:C:CC	donor_gain	1.0000

AlphaMissense

5124 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:83392605:C:A	W539C	1.000
7:83392605:C:G	W539C	1.000
7:83392611:A:C	C537W	1.000
7:83402749:A:C	C342W	1.000
7:83405991:G:C	C294W	1.000
7:83405993:A:G	C294R	1.000
7:83367728:C:G	C729S	0.999
7:83367728:C:T	C729Y	0.999
7:83367729:A:T	C729S	0.999
7:83367952:G:C	C654W	0.999
7:83367953:C:G	C654S	0.999
7:83367954:A:T	C654S	0.999
7:83367960:A:C	Y652D	0.999
7:83385365:A:G	C602R	0.999
7:83392590:G:C	C544W	0.999
7:83392591:C:G	C544S	0.999
7:83392591:C:T	C544Y	0.999
7:83392592:A:G	C544R	0.999
7:83392592:A:T	C544S	0.999
7:83392607:A:G	W539R	0.999
7:83392607:A:T	W539R	0.999
7:83392612:C:A	C537F	0.999
7:83392612:C:G	C537S	0.999
7:83392612:C:T	C537Y	0.999
7:83392613:A:G	C537R	0.999
7:83392613:A:T	C537S	0.999
7:83392621:T:C	D534G	0.999
7:83392624:C:G	R533P	0.999
7:83392635:G:C	C529W	0.999
7:83392665:A:C	C519W	0.999

dbSNP variants (sampled 300 via entrez): RS1000000382 (7:83539660 T>A,C), RS1000008781 (7:83387562 A>G,T), RS1000009245 (7:83422381 A>G), RS1000013820 (7:83503413 G>A), RS1000046437 (7:83455504 T>C,G), RS1000051478 (7:83622857 A>G), RS1000065680 (7:83543830 G>A), RS1000068753 (7:83429383 A>G), RS1000081144 (7:83415549 A>G), RS1000085618 (7:83608170 G>A), RS1000086301 (7:83554432 G>A,C,T), RS1000097742 (7:83461614 G>C), RS1000107322 (7:83505944 A>G), RS1000108150 (7:83587648 A>G), RS1000108720 (7:83373934 C>T)

Disease associations

OMIM: gene MIM:608166 | disease phenotypes: MIM:146110, MIM:115200, MIM:612370, MIM:266600

GenCC curated gene-disease

Disease	Classification	Inheritance
CHD7-related CHARGE syndrome	Moderate	Autosomal dominant
Kallmann syndrome	Limited	Autosomal dominant
complex neurodevelopmental disorder	Limited	Autosomal dominant
CHARGE syndrome	Limited	Autosomal dominant

Mondo (10): CHARGE syndrome (MONDO:0008965), hypogonadotropic hypogonadism 7 with or without anosmia (MONDO:0007794), dilated cardiomyopathy 1A (MONDO:0007269), hypogonadotropic hypogonadism 5 with or without anosmia (MONDO:0012880), isolated anophthalmia-microphthalmia syndrome (MONDO:0016764), inflammatory bowel disease (MONDO:0005265), amenorrhea (MONDO:0001836), Kallmann syndrome (MONDO:0018800), complex neurodevelopmental disorder (MONDO:0100038), CHD7-related CHARGE syndrome (MONDO:1010178)

Orphanet (6): CHARGE syndrome (Orphanet:138), Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432), Familial dilated cardiomyopathy with conduction defect due to LMNA mutation (Orphanet:300751), Kallmann syndrome (Orphanet:478), Isolated microphthalmia-anophthalmia-coloboma (Orphanet:2542), Rare inflammatory bowel disease (Orphanet:104012)

HPO phenotypes

103 total (30 of 103 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000048	Bifid scrotum
HP:0000054	Micropenis
HP:0000066	Labial hypoplasia
HP:0000076	Vesicoureteral reflux
HP:0000085	Horseshoe kidney
HP:0000126	Hydronephrosis
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000204	Cleft upper lip
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000358	Posteriorly rotated ears
HP:0000359	Abnormality of the inner ear
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000384	Preauricular skin tag
HP:0000396	Overfolded helix
HP:0000453	Choanal atresia
HP:0000458	Anosmia
HP:0000465	Webbed neck
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000504	Abnormality of vision

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002576_6	Epithelial ovarian cancer	4.000000e-06
GCST003482_2	Asthma (childhood onset)	5.000000e-06
GCST005790_7	Rosacea symptom severity	8.000000e-06
GCST006110_34	Nose morphology	8.000000e-06
GCST006288_646	Heel bone mineral density	5.000000e-10
GCST006288_753	Heel bone mineral density	3.000000e-07
GCST006585_2339	Blood protein levels	2.000000e-50
GCST006585_425	Blood protein levels	0.000000e+00
GCST006979_128	Heel bone mineral density	6.000000e-17
GCST008891_9	Cognitive performance (processing speed)	3.000000e-06
GCST009218_18	Lateral ventricle temporal horn volume	7.000000e-06
GCST009391_215	Metabolite levels	4.000000e-06
GCST009391_994	Metabolite levels	7.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009180	rosacea severity measurement
EFO:0009270	heel bone mineral density
EFO:0004363	information processing speed
EFO:0010475	deoxycholate measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D058747	CHARGE Syndrome	C09.218.458.341.186.500.250; C10.597.751.418.341.186.500.250; C10.597.751.941.162.625.250; C11.270.147.500; C11.966.075.375.250; C16.131.077.299.250; C16.320.165; C23.888.592.763.393.341.186.500.500; C23.888.592.763.941.162.625.500
D015212	Inflammatory Bowel Diseases	C06.405.205.731; C06.405.469.432
D017436	Kallmann Syndrome	C12.050.351.875.253.096.750; C12.200.706.316.096.750; C12.800.316.096.750; C16.131.939.316.096.750; C16.320.467; C19.391.119.096.750; C19.391.482.600
C562785	Idiopathic Hypogonadotropic Hypogonadism (supp.)
C567220	Kallmann Syndrome 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	affects methylation, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
(+)-JQ1 compound	decreases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Particulate Matter	increases expression, decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	increases reaction, affects binding	1
3-nitrobenzanthrone	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03687606	PHASE4	UNKNOWN	Efficacy and Safety of Long Term Use of hCG or hCG Plus hMG in Males With Isolated Hypogonadotropic Hypogonadism (IHH)
NCT00167882	PHASE4	COMPLETED	The Influence of 5-Aminosalicylates on Thiopurine Metabolite Levels
NCT00205062	PHASE4	TERMINATED	Positron Emission Tomography (PET)-Computed Tomography (CT) in Inflammatory Bowel Disease (IBD)
NCT00567593	PHASE4	COMPLETED	Gene Regulation by Thiazolidinediones
NCT00746395	PHASE4	COMPLETED	Randomized, Placebo-controlled Trial of Lubiprostone as a Preparation for Capsule Endoscopy
NCT01034358	PHASE4	COMPLETED	Immune Response to the Human Papillomavirus Vaccine in Young Women With Inflammatory Bowel Disease
NCT01056913	PHASE4	COMPLETED	NITI CAR27 (ColonRing) Compression Anastomosis in Colorectal Surgery
NCT01067547	PHASE4	COMPLETED	A Trial of Iron Replacement in Patients With Iron Deficiency.
NCT01341808	PHASE4	COMPLETED	Immunogenicity of Hepatitis A Vaccine in Inflammatory Bowel Disease (IBD) Patients
NCT01908283	PHASE4	COMPLETED	Induction of Immunity Against Streptococcus Pneumoniae in Adults With Inflammatory Bowel Disease
NCT01934088	PHASE4	COMPLETED	Satisfaction With Nurse Administered Propofol Sedation vs. Midazolam With Fentanyl Sedation for Endoscopy
NCT02162862	PHASE4	COMPLETED	Treating Disrupted Sleep in Individuals With Inflammatory Bowel Disease
NCT02248337	PHASE4	COMPLETED	Low Volume Colon Preparation for IBD
NCT02281799	PHASE4	WITHDRAWN	Thiopurine Induced Pancreatitis in IBD Patients
NCT02392286	PHASE4	TERMINATED	Corticosteroid Dosage for Crohn’s Disease Flare
NCT02437591	PHASE4	COMPLETED	Study to Evaluate the Pharmacokinetics of Fidaxomicin in Inflammatory Bowel Disease (IBD) Subjects With Clostridium Difficile Infection (CDI)
NCT02453776	PHASE4	COMPLETED	Precision Dosing of Infliximab Versus Conventional Dosing of Infliximab
NCT02461758	PHASE4	COMPLETED	Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory Bowel Disease Patients
NCT02566889	PHASE4	TERMINATED	An Efficacy and Safety Study of Infliximab Dose Escalation in Pediatric Participants With Inflammatory Bowel Disease
NCT02774057	PHASE4	UNKNOWN	Trial of Captafer® vs. Oral Iron Sulfate in the Treatment of Iron Deficiency Anemia in Patients With IBD
NCT02806206	PHASE4	UNKNOWN	Prucalopride Prior to Small Bowel Capsule Endoscopy
NCT02946203	PHASE4	COMPLETED	Comparison of VoLumen and Breeza Oral Contrast Agents in Pediatric Patients
NCT02994836	PHASE4	COMPLETED	GIS-SUSANTI-TNF-2015 (Anti-TNF Discontinuation )
NCT03220841	PHASE4	UNKNOWN	Stricture Definition and Treatment (STRIDENT) Drug Therapy Study
NCT03351972	PHASE4	COMPLETED	Differences in Preparation for Small Bowel Capsule Endoscopy
NCT03466983	PHASE4	COMPLETED	A Trial Comparing the Incidence of Hypophosphatemia in Relation to Treatment With Iron Isomaltoside and Ferric Carboxymaltose in Subjects With Iron Deficiency Anaemia Due to Inflammatory Bowel Disease
NCT03591770	PHASE4	TERMINATED	Shingrix Vaccine in Patients With Moderate to Severe Ulcerative Colitis on Tofacitinib
NCT03629379	PHASE4	COMPLETED	Response to Ustekinumab for Anti-tnf Induced Psoriasiform Skin Lesions
NCT03723447	PHASE4	COMPLETED	Intraoperative TAP Block With Bupivacaine/Dexamethasone Against Liposomal Bupivacaine (Exparel®)
NCT03798691	PHASE4	COMPLETED	Immunogenicity of Herpes Zoster Subunit Vaccine in Inflammatory Bowel Disease Patients Treated With Vedolizumab
NCT03860012	PHASE4	UNKNOWN	Folic Acid in Pediatric Inflammatory Bowel Disease
NCT03885713	PHASE4	COMPLETED	Identification of Predictive Biomarkers for Response to Biologic Therapies and Tofacitinib in Inflammatory Bowel Disease
NCT03917303	PHASE4	RECRUITING	Control Crohn Safe Trial
NCT04045782	PHASE4	COMPLETED	Evaluation of the Safety and Effectiveness of Switching From Humira® to Imraldi® in Flanders
NCT04304950	PHASE4	COMPLETED	Chronotherapy in Inflammatory Bowel Disease
NCT04626947	PHASE4	TERMINATED	Prevention of Recurrent Clostridium Difficile Infection (CDI) in Patients With Inflammatory Bowel Disease (IBD).
NCT04646187	PHASE4	ENROLLING_BY_INVITATION	De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease
NCT04835506	PHASE4	ACTIVE_NOT_RECRUITING	Proactive Infliximab Optimization Using a Pharmacokinetic Dashboard Versus Standard of Care in Patients With Inflammatory Bowel Disease: The OPTIMIZE Trial