NTN3

Summary

NTN3 (netrin 3, HGNC:8030) is a protein-coding gene on chromosome 16p13.3, encoding Netrin-3 (O00634). Netrins control guidance of CNS commissural axons and peripheral motor axons.

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in Golgi apparatus and extracellular region.

Source: NCBI Gene 4917 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 113 total
• MANE Select transcript: NM_006181

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8030
Approved symbol	NTN3
Name	netrin 3
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000162068
Ensembl biotype	protein_coding
OMIM	602349
Entrez	4917

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000293973

RefSeq mRNA: 1 — MANE Select: NM_006181 NM_006181

CCDS: CCDS10469

Canonical transcript exons

ENST00000293973 — 6 exons

Exon	Start	End
ENSE00001062436	2473268	2473318
ENSE00001062437	2472985	2473134
ENSE00001118862	2472701	2472889
ENSE00001197092	2473429	2473503
ENSE00001235511	2473756	2474145
ENSE00001235520	2471297	2472629

Expression profiles

Bgee: expression breadth broad, 56 present calls, max score 85.61.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9891 / max 114.5304, expressed in 307 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152226	0.8415	281
152227	0.0779	20
152228	0.0402	12
152229	0.0296	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	85.61	silver quality
triceps brachii	UBERON:0001509	64.75	gold quality
gluteal muscle	UBERON:0002000	64.57	gold quality
ventricular zone	UBERON:0003053	62.49	gold quality
ganglionic eminence	UBERON:0004023	60.86	gold quality
buccal mucosa cell	CL:0002336	57.07	gold quality
cortical plate	UBERON:0005343	56.41	gold quality
tendon of biceps brachii	UBERON:0008188	56.40	silver quality
medial globus pallidus	UBERON:0002477	55.77	gold quality
epithelial cell of pancreas	CL:0000083	55.63	silver quality
embryo	UBERON:0000922	55.62	gold quality
stromal cell of endometrium	CL:0002255	54.92	gold quality
granulocyte	CL:0000094	53.60	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	53.33	gold quality
decidua	UBERON:0002450	52.56	gold quality
globus pallidus	UBERON:0001875	52.41	gold quality
nasal cavity epithelium	UBERON:0005384	52.11	gold quality
parotid gland	UBERON:0001831	51.54	gold quality
skin of hip	UBERON:0001554	50.49	silver quality
quadriceps femoris	UBERON:0001377	50.47	gold quality
vastus lateralis	UBERON:0001379	50.33	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	49.95	gold quality
skeletal muscle tissue	UBERON:0001134	49.36	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.33

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

Literature-anchored findings (GeneRIF, showing 2)

• an autocrine function for netrin-1 and netrin-3 in U87 and U373 cells that slows migration (PMID:21980448)
• Netrin signaling mediates survival of dormant epithelial ovarian cancer cells. (PMID:39023520)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ntn2	ENSDARG00000076748
mus_musculus	Ntn3	ENSMUSG00000117406
rattus_norvegicus	Ntn3	ENSRNOG00000006970
drosophila_melanogaster	NetA	FBGN0015773
drosophila_melanogaster	NetB	FBGN0015774
caenorhabditis_elegans		WBGENE00006746

Paralogs (27): USH2A (ENSG00000042781), LAMC3 (ENSG00000050555), LAMA3 (ENSG00000053747), LAMC2 (ENSG00000058085), NTN1 (ENSG00000065320), NTN4 (ENSG00000074527), ATRN (ENSG00000088812), LAMB4 (ENSG00000091128), LAMB1 (ENSG00000091136), LAMA1 (ENSG00000101680), MEGF8 (ENSG00000105429), MEGF9 (ENSG00000106780), ATRNL1 (ENSG00000107518), LAMA4 (ENSG00000112769), LAMA5 (ENSG00000130702), LAMC1 (ENSG00000135862), NTN5 (ENSG00000142233), HSPG2 (ENSG00000142798), TMEFF2 (ENSG00000144339), NTNG1 (ENSG00000162631), EGFLAM (ENSG00000164318), LAMB2 (ENSG00000172037), AGRN (ENSG00000188157), NTNG2 (ENSG00000196358), LAMA2 (ENSG00000196569), LAMB3 (ENSG00000196878), TMEFF1 (ENSG00000241697)

Protein

Protein identifiers

Netrin-3 — O00634 (reviewed: O00634)

Alternative names: Netrin-2-like protein

All UniProt accessions (1): O00634

UniProt curated annotations — full annotation on UniProt →

Function. Netrins control guidance of CNS commissural axons and peripheral motor axons.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Spinal cord.

RefSeq proteins (1): NP_006172* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001134	Netrin_domain	Domain
IPR002049	LE_dom	Domain
IPR008211	Laminin_N	Domain
IPR008993	TIMP-like_OB-fold	Homologous_superfamily
IPR018933	Netrin_module_non-TIMP	Domain
IPR050440	Laminin/Netrin_ECM	Family
IPR056863	LMN_ATRN_NET-like_EGF	Domain

Pfam: PF00053, PF00055, PF01759, PF24973

UniProt features (27 total): disulfide bond 15, domain 5, glycosylation site 2, signal peptide 1, chain 1, sequence variant 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00634-F1	87.82	0.69

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 (15): 92–125, 255–264, 257–274, 276–285, 288–308, 311–320, 313–338, 341–350, 353–371, 374–386, 376–393, 395–404, 407–421, 441–514, 460–577

Glycosylation sites (2): 387, 104

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-525793	Myogenesis
R-HSA-1266738	Developmental Biology

MSigDB gene sets: 84 (showing top): GOBP_NEUROGENESIS, GGGTGGRR_PAX4_03, USF_C, MYCMAX_01, ZIC1_01, MODULE_157, MORF_RAB3A, GOBP_CELL_PROJECTION_ORGANIZATION, MORF_WNT1, GOMF_SIGNALING_RECEPTOR_BINDING, DANG_BOUND_BY_MYC, AP4_01, RYTGCNWTGGNR_UNKNOWN, WGGAATGY_TEF1_Q6, MODULE_220

GO Biological Process (3): regulation of transcription by RNA polymerase II (GO:0006357), axon guidance (GO:0007411), axonogenesis (GO:0007409)

GO Molecular Function (4): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), Golgi apparatus (GO:0005794), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
axonogenesis	1
neuron projection guidance	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
protein binding	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

722 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NTN3	NEO1	Q92859	885
NTN3	UNC5C	O95185	786
NTN3	UNC5B	Q8IZJ1	729
NTN3	UNC5A	Q6ZN44	619
NTN3	UNC5D	Q6UXZ4	540
NTN3	DCC	P43146	499
NTN3	GAS1	P54826	488
NTN3	MRI1	Q9BV20	456
NTN3	RNF26	Q9BY78	450
NTN3	CDH2	P19022	438
NTN3	CRB2	Q5IJ48	430
NTN3	HTR5A	P47898	427
NTN3	TPPP2	P59282	421
NTN3	COL18A1	P39060	418
NTN3	SLC18A3	Q16572	386

IntAct

4 interactions, top by confidence:

A	B	Type	Score
DRAXIN	NTN3	psi-mi:“MI:0915”(physical association)	0.400
NTN3	DRAXIN	psi-mi:“MI:0915”(physical association)	0.400
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (5): NTN3 (Affinity Capture-RNA), NTN3 (Affinity Capture-MS), NTN3 (Affinity Capture-MS), NTN3 (Affinity Capture-RNA), NTN3 (Positive Genetic)

ESM2 similar proteins: A0A061IR73, A6H687, A6NKF1, D3KCC4, E1BD59, G3MY25, G3MZC5, O00634, O75064, P0C5W1, P20863, P27539, P52824, P54777, Q002B5, Q08DM2, Q0VCE3, Q13608, Q17RN3, Q2TBW5, Q3U0S6, Q4VYA0, Q53EQ6, Q561R2, Q568Y2, Q5BK61, Q5JR98, Q5RE82, Q5U651, Q6F5E8, Q6NY19, Q6ZS72, Q8BH83, Q8C052, Q8CDY7, Q8VIM9, Q8WZA9, Q90343, Q90ZN1, Q92985

Diamond homologs: A0JP86, A2ASQ1, G5ECE3, O00468, O00634, O09118, O15230, O75445, O75882, O95631, P02468, P11047, P15215, P19137, P24043, P25304, P25391, P31696, P34710, P97927, Q00174, Q01635, Q13751, Q13753, Q16363, Q16787, Q18823, Q19981, Q1LVF0, Q24567, Q24568, Q27262, Q2HXW4, Q2QI47, Q5RB89, Q5VV63, Q60675, Q61001, Q61087, Q61092

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NTN3	“up-regulates activity”	NEO1	binding
NTN3	“up-regulates activity”	UNC5	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	103
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

580 predictions. Top by Δscore:

Variant	Effect	Δscore
16:2472886:AGGGG:A	donor_loss	1.0000
16:2472887:GGG:G	donor_gain	1.0000
16:2472888:GG:G	donor_gain	1.0000
16:2472888:GGG:G	donor_gain	1.0000
16:2472889:GG:G	donor_gain	1.0000
16:2472889:GGTGA:G	donor_loss	1.0000
16:2472890:GTGAG:G	donor_loss	1.0000
16:2472891:T:A	donor_loss	1.0000
16:2472983:A:AG	acceptor_gain	1.0000
16:2472984:G:GG	acceptor_gain	1.0000
16:2473135:G:GG	donor_gain	1.0000
16:2472862:GCCC:G	donor_gain	0.9900
16:2472872:ACC:A	donor_gain	0.9900
16:2472889:G:T	donor_gain	0.9900
16:2472892:GA:G	donor_loss	0.9900
16:2472984:GC:G	acceptor_gain	0.9900
16:2472984:GCC:G	acceptor_gain	0.9900
16:2472984:GCCT:G	acceptor_gain	0.9900
16:2473131:GTTA:G	donor_gain	0.9900
16:2473317:GG:G	donor_gain	0.9900
16:2473318:GG:G	donor_gain	0.9900
16:2473320:T:A	donor_loss	0.9900
16:2473427:A:AG	acceptor_gain	0.9900
16:2473428:G:GG	acceptor_gain	0.9900
16:2473428:GACT:G	acceptor_gain	0.9900
16:2472699:A:AG	acceptor_gain	0.9800
16:2472700:G:GG	acceptor_gain	0.9800
16:2472700:GCTT:G	acceptor_gain	0.9800
16:2472834:G:GT	donor_gain	0.9800
16:2472835:G:T	donor_gain	0.9800

AlphaMissense

3697 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:2473078:G:A	C404Y	1.000
16:2471980:G:C	W93C	0.999
16:2471980:G:T	W93C	0.999
16:2472592:G:C	W297C	0.999
16:2472592:G:T	W297C	0.999
16:2472736:T:C	F322L	0.999
16:2472738:C:A	F322L	0.999
16:2472738:C:G	F322L	0.999
16:2472784:T:A	C338S	0.999
16:2472785:G:C	C338S	0.999
16:2472821:G:A	C350Y	0.999
16:2472821:G:T	C350F	0.999
16:2472822:C:G	C350W	0.999
16:2472994:G:A	C376Y	0.999
16:2473005:G:T	G380C	0.999
16:2473023:T:A	C386S	0.999
16:2473024:G:A	C386Y	0.999
16:2473024:G:C	C386S	0.999
16:2473025:C:G	C386W	0.999
16:2473044:T:A	C393S	0.999
16:2473044:T:C	C393R	0.999
16:2473045:G:C	C393S	0.999
16:2473050:T:A	C395S	0.999
16:2473051:G:A	C395Y	0.999
16:2473051:G:C	C395S	0.999
16:2473055:G:C	K396N	0.999
16:2473055:G:T	K396N	0.999
16:2473077:T:A	C404S	0.999
16:2473077:T:C	C404R	0.999
16:2473078:G:C	C404S	0.999

dbSNP variants (sampled 300 via entrez): RS1000849271 (16:2469950 G>A,T), RS1001149456 (16:2473912 C>A,G,T), RS1001337579 (16:2470022 C>G), RS1001517211 (16:2474087 G>A,C,T), RS1002954837 (16:2471439 C>T), RS1003005094 (16:2471251 G>A), RS1003938859 (16:2474329 C>T), RS1004224877 (16:2470877 G>T), RS1004315415 (16:2469297 A>T), RS1004815200 (16:2470248 G>A), RS1006072348 (16:2474378 G>A), RS1006352329 (16:2471798 G>A), RS1006878715 (16:2471514 T>C), RS1006899859 (16:2471468 G>A), RS1007187062 (16:2474117 G>A)

Disease associations

OMIM: gene MIM:602349 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
propionaldehyde	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
1-nitropyrene	decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Chelating Agents	affects binding, decreases expression	1
Copper	affects binding, decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases methylation	1
Copper Sulfate	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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