LRFN3

Summary

LRFN3 (leucine rich repeat and fibronectin type III domain containing 3, HGNC:28370) is a protein-coding gene on chromosome 19q13.12, encoding Leucine-rich repeat and fibronectin type-III domain-containing protein 3 (Q9BTN0). Cell adhesion molecule that mediates homophilic cell-cell adhesion in a Ca(2+)-independent manner.

Predicted to be involved in regulation of presynapse assembly; regulation of synaptic membrane adhesion; and synaptic membrane adhesion. Predicted to be located in plasma membrane. Predicted to be active in cell surface; glutamatergic synapse; and synaptic membrane.

Source: NCBI Gene 79414 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 117 total
• MANE Select transcript: NM_024509

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28370
Approved symbol	LRFN3
Name	leucine rich repeat and fibronectin type III domain containing 3
Location	19q13.12
Locus type	gene with protein product
Status	Approved
Aliases	MGC2656, SALM4, FIGLER1
Ensembl gene	ENSG00000126243
Ensembl biotype	protein_coding
OMIM	612809
Entrez	79414

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000246529, ENST00000585876, ENST00000587257, ENST00000588831

RefSeq mRNA: 1 — MANE Select: NM_024509 NM_024509

CCDS: CCDS12483

Canonical transcript exons

ENST00000246529 — 3 exons

Exon	Start	End
ENSE00000862903	35939410	35940840
ENSE00000862904	35944548	35946624
ENSE00001057338	35936374	35937555

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 84.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.9400 / max 168.8062, expressed in 1586 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175446	7.6198	1578
175447	0.9327	616
175448	0.2718	99
175445	0.1158	51

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	84.51	gold quality
thoracic aorta	UBERON:0001515	80.65	gold quality
ascending aorta	UBERON:0001496	80.60	gold quality
right ovary	UBERON:0002118	80.54	gold quality
adenohypophysis	UBERON:0002196	80.08	gold quality
ectocervix	UBERON:0012249	79.96	gold quality
right coronary artery	UBERON:0001625	79.86	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.82	silver quality
aorta	UBERON:0000947	79.42	gold quality
left ovary	UBERON:0002119	79.29	gold quality
body of uterus	UBERON:0009853	79.27	gold quality
descending thoracic aorta	UBERON:0002345	79.26	gold quality
prefrontal cortex	UBERON:0000451	79.23	gold quality
left uterine tube	UBERON:0001303	79.20	gold quality
right frontal lobe	UBERON:0002810	79.03	gold quality
left coronary artery	UBERON:0001626	78.96	gold quality
popliteal artery	UBERON:0002250	78.89	gold quality
tibial artery	UBERON:0007610	78.87	gold quality
endocervix	UBERON:0000458	78.82	gold quality
mucosa of stomach	UBERON:0001199	78.75	gold quality
gastrocnemius	UBERON:0001388	78.74	gold quality
stromal cell of endometrium	CL:0002255	78.22	gold quality
pituitary gland	UBERON:0000007	77.84	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	77.39	gold quality
apex of heart	UBERON:0002098	77.19	gold quality
muscle of leg	UBERON:0001383	77.11	gold quality
right adrenal gland	UBERON:0001233	77.06	gold quality
mucosa of transverse colon	UBERON:0004991	76.98	gold quality
coronary artery	UBERON:0001621	76.95	gold quality
lower esophagus muscularis layer	UBERON:0035833	76.70	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.40

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting LRFN3, 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-3148	99.97	75.06	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
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
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-7855-5P	97.39	67.18	925
HSA-MIR-759	96.16	66.77	873
HSA-MIR-3117-3P	95.96	67.82	473
HSA-MIR-8083	95.93	67.55	694
HSA-MIR-4453	95.61	65.84	436
HSA-MIR-4538	95.61	65.34	449
HSA-MIR-10396A-3P	93.99	62.06	94
HSA-MIR-10396B-3P	93.99	62.06	94
HSA-MIR-5708	90.54	64.01	66

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:172282	ENSDARG00000105059
mus_musculus	Lrfn3	ENSMUSG00000036957
rattus_norvegicus	Lrfn3	ENSRNOG00000020839

Paralogs (25): SLITRK3 (ENSG00000121871), LRFN1 (ENSG00000128011), SLIT2 (ENSG00000145147), LRFN2 (ENSG00000156564), LRRC38 (ENSG00000162494), SLITRK5 (ENSG00000165300), LRFN5 (ENSG00000165379), LRTM2 (ENSG00000166159), LINGO1 (ENSG00000169783), LRRN2 (ENSG00000170382), LRRN3 (ENSG00000173114), LRFN4 (ENSG00000173621), LINGO2 (ENSG00000174482), LRRN1 (ENSG00000175928), SLITRK1 (ENSG00000178235), GP5 (ENSG00000178732), SLITRK4 (ENSG00000179542), LRRC55 (ENSG00000183908), SLIT3 (ENSG00000184347), SLITRK6 (ENSG00000184564), SLITRK2 (ENSG00000185985), LRRC70 (ENSG00000186105), SLIT1 (ENSG00000187122), TLR9 (ENSG00000239732), TPBGL (ENSG00000261594)

Protein

Protein identifiers

Leucine-rich repeat and fibronectin type-III domain-containing protein 3 — Q9BTN0 (reviewed: Q9BTN0)

Alternative names: Synaptic adhesion-like molecule 4

All UniProt accessions (1): Q9BTN0

UniProt curated annotations — full annotation on UniProt →

Function. Cell adhesion molecule that mediates homophilic cell-cell adhesion in a Ca(2+)-independent manner. Promotes neurite outgrowth in hippocampal neurons.

Subunit / interactions. Can form heteromeric complexes with LRFN1, LRFN2, LRFN4 and LRFN5. Able to form homomeric complexes across cell junctions, between adjacent cells. Does not interact with DLG4.

Subcellular location. Cell membrane. Cell projection. Axon. Dendrite. Synapse. Presynaptic cell membrane. Postsynaptic cell membrane.

Post-translational modifications. N-glycosylated.

Domain organisation. Lacks a cytoplasmic PDZ-binding domain, which has been implicated in function of related Lrfn proteins.

Similarity. Belongs to the LRFN family.

RefSeq proteins (1): NP_078785* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000483	Cys-rich_flank_reg_C	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR003961	FN3_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050467	LRFN	Family

Pfam: PF00041, PF07679, PF13855

UniProt features (26 total): repeat 7, glycosylation site 5, domain 4, topological domain 2, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1, disulfide bond 1, sequence variant 1, sequence conflict 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BTN0-F1	78.33	0.51

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 (1): 317–366

Glycosylation sites (5): 81, 339, 348, 393, 462

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8849932	Synaptic adhesion-like molecules
R-HSA-112316	Neuronal System
R-HSA-6794362	Protein-protein interactions at synapses

MSigDB gene sets: 108 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_SYNAPSE_ASSEMBLY, GOCC_CELL_SURFACE, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELL_CELL_ADHESION, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_REGULATION_OF_SYNAPSE_STRUCTURE_OR_ACTIVITY, BENPORATH_NOS_TARGETS, GOBP_CELL_JUNCTION_ASSEMBLY, GOCC_NEURON_PROJECTION, CCCNNGGGAR_OLF1_01, GOCC_POSTSYNAPSE, BENPORATH_OCT4_TARGETS

GO Biological Process (4): regulation of synaptic membrane adhesion (GO:0099179), synaptic membrane adhesion (GO:0099560), regulation of presynapse assembly (GO:1905606), cell adhesion (GO:0007155)

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

GO Cellular Component (13): plasma membrane (GO:0005886), cell surface (GO:0009986), axon (GO:0030424), dendrite (GO:0030425), presynaptic active zone membrane (GO:0048787), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), membrane (GO:0016020), presynaptic membrane (GO:0042734), cell projection (GO:0042995), synapse (GO:0045202), postsynaptic membrane (GO:0045211), postsynaptic specialization membrane (GO:0099634)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Protein-protein interactions at synapses	1
Neuronal System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
synaptic membrane	4
cellular anatomical structure	3
neuron projection	2
postsynaptic membrane	2
regulation of cell-cell adhesion	1
regulation of synapse organization	1
synaptic membrane adhesion	1
synapse organization	1
cell-cell adhesion	1
regulation of synapse assembly	1
presynapse assembly	1
regulation of presynapse organization	1
cellular process	1
binding	1
membrane	1
cell periphery	1
dendritic tree	1
presynaptic membrane	1
presynaptic active zone	1
postsynaptic density	1
postsynaptic specialization membrane	1
synapse	1
presynapse	1
cell junction	1
postsynapse	1
postsynaptic specialization	1

Protein interactions and networks

STRING

838 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRFN3	DLG4	P78352	726
LRFN3	PTPRF	P10586	590
LRFN3	PTPRS	Q13332	518
LRFN3	TTC9B	Q8N6N2	500
LRFN3	FN1	P02751	478
LRFN3	IRGQ	Q8WZA9	471
LRFN3	IL1RAPL1	Q9NZN1	439
LRFN3	ABRACL	Q9P1F3	435
LRFN3	DMAC2	Q9NW81	431
LRFN3	LRFN5	Q96NI6	424
LRFN3	TULP2	O00295	387
LRFN3	SBK1	Q52WX2	385
LRFN3	ALKBH6	Q3KRA9	375
LRFN3	OR6N2	Q8NGY6	375
LRFN3	NRXN2	Q9P2S2	358

IntAct

77 interactions, top by confidence:

A	B	Type	Score
CRIPTO	AIP	psi-mi:“MI:0914”(association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
SLC39A5	TMEM223	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LRRTM1	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ADAM21	PLXNA2	psi-mi:“MI:0914”(association)	0.530
VAMP5	NBAS	psi-mi:“MI:0914”(association)	0.530
PON2	NPC1	psi-mi:“MI:0914”(association)	0.530
C1orf54	EXTL3	psi-mi:“MI:0914”(association)	0.530
TNFSF8	LGALS8	psi-mi:“MI:0914”(association)	0.530
VEGFB	LAMB2	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
FLVCR1	TNFRSF10B	psi-mi:“MI:0914”(association)	0.530
PTPRD	LRFN3	psi-mi:“MI:0407”(direct interaction)	0.440
PTPRS	LRFN3	psi-mi:“MI:0407”(direct interaction)	0.440
LRRTM1	TMEM223	psi-mi:“MI:0914”(association)	0.350
HTR3C	TMEM223	psi-mi:“MI:0914”(association)	0.350
TMPRSS11B		psi-mi:“MI:0914”(association)	0.350
TMPRSS3	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
LYPD4	DPYSL4	psi-mi:“MI:0914”(association)	0.350
MPPE1	ADAM10	psi-mi:“MI:0914”(association)	0.350
PTCH1	PLXNB2	psi-mi:“MI:0914”(association)	0.350
ADAM21	PLXNB2	psi-mi:“MI:0914”(association)	0.350
DPEP2	KDELR3	psi-mi:“MI:0914”(association)	0.350

BioGRID (75): LRFN3 (Affinity Capture-MS), LRFN3 (Affinity Capture-MS), LRFN3 (Affinity Capture-MS), LRFN3 (Affinity Capture-MS), LRFN3 (Affinity Capture-MS), LRFN3 (Affinity Capture-MS), LRFN3 (Affinity Capture-MS), LRFN3 (Affinity Capture-MS), LRFN3 (Affinity Capture-MS), LRFN3 (Affinity Capture-MS), LRFN3 (Affinity Capture-MS), LRFN3 (Affinity Capture-MS), LRFN3 (Affinity Capture-MS), LRFN3 (Affinity Capture-MS), LRFN3 (Affinity Capture-MS)

ESM2 similar proteins: A2A9Q0, A5PKD8, B0BNK7, D2HFT7, D4ABX8, E9Q7T7, O75325, O94819, P0C7J6, P0DKB5, Q04785, Q13641, Q1RMS4, Q24JP5, Q28730, Q2I0M4, Q2WF71, Q460M5, Q4R8Y9, Q50LG9, Q5PQV5, Q6NUI6, Q6PJG9, Q6UKI2, Q7M6Z0, Q80TG9, Q80W15, Q80WD1, Q80XU8, Q86UN3, Q86WK7, Q8BHA1, Q8BLY3, Q8BNW9, Q8C013, Q8WX77, Q96PE1, Q9BE71, Q9BTN0, Q9BY71

Diamond homologs: A0A1Y9G8H0, A0A452E9Y6, A1KZ92, A2A8L5, A2AJ76, A4IFW2, A4IGL7, A4IIW9, A5JUY8, A7MBJ4, A8WGA3, A8WQH2, B0BNK7, B3A0P3, D2HFT7, D3YXG0, D4A1J9, D4ABX8, G5EBF1, G5EG78, H2A0M7, O15146, O35158, O55005, O89026, P05164, P07202, P09933, P0C6S8, P0C7J6, P11247, P11678, P14650, P16621, P22079, P23468, P35419, P49290, P70193, P80025

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
LRFN3	up-regulates	Neurite_outgrowth

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	108
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

613 predictions. Top by Δscore:

Variant	Effect	Δscore
19:35944542:CTGCA:C	acceptor_loss	1.0000
19:35944543:TGCAG:T	acceptor_loss	1.0000
19:35944544:GCAG:G	acceptor_loss	1.0000
19:35944545:CA:C	acceptor_loss	1.0000
19:35944546:A:AG	acceptor_gain	1.0000
19:35944546:A:T	acceptor_loss	1.0000
19:35944546:AGGAT:A	acceptor_gain	1.0000
19:35944547:G:GC	acceptor_gain	1.0000
19:35944547:GGA:G	acceptor_gain	1.0000
19:35944547:GGATG:G	acceptor_gain	1.0000
19:35935780:CAGG:C	donor_loss	0.9900
19:35935781:AGG:A	donor_loss	0.9900
19:35935782:GGTAA:G	donor_loss	0.9900
19:35935783:G:A	donor_loss	0.9900
19:35935784:T:G	donor_loss	0.9900
19:35944546:AG:A	acceptor_gain	0.9900
19:35944547:GG:G	acceptor_gain	0.9900
19:35944547:GGAT:G	acceptor_gain	0.9900
19:35939404:CCGCA:C	acceptor_loss	0.9800
19:35939405:CGCA:C	acceptor_loss	0.9800
19:35939406:GCAGG:G	acceptor_loss	0.9800
19:35939407:CA:C	acceptor_loss	0.9800
19:35939408:AGGA:A	acceptor_loss	0.9800
19:35939409:G:GA	acceptor_loss	0.9800
19:35939408:A:AG	acceptor_gain	0.9700
19:35939408:AG:A	acceptor_gain	0.9700
19:35939409:G:GG	acceptor_gain	0.9700
19:35939409:GG:G	acceptor_gain	0.9700
19:35940836:TACAG:T	donor_loss	0.9700
19:35940837:ACAG:A	donor_loss	0.9700

AlphaMissense

3945 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:35939703:A:T	N93I	1.000
19:35939704:C:A	N93K	1.000
19:35939704:C:G	N93K	1.000
19:35939922:A:T	N166I	1.000
19:35939923:C:A	N166K	1.000
19:35939923:C:G	N166K	1.000
19:35940067:C:A	N214K	1.000
19:35940067:C:G	N214K	1.000
19:35940412:G:C	W329C	1.000
19:35940412:G:T	W329C	1.000
19:35940535:T:A	N370K	1.000
19:35940535:T:G	N370K	1.000
19:35940760:G:C	W445C	1.000
19:35940760:G:T	W445C	1.000
19:35939632:C:A	N69K	0.999
19:35939632:C:G	N69K	0.999
19:35939688:T:C	L88P	0.999
19:35939702:A:T	N93Y	0.999
19:35939776:C:A	N117K	0.999
19:35939776:C:G	N117K	0.999
19:35939823:T:G	L133W	0.999
19:35939832:T:C	L136P	0.999
19:35939848:C:A	N141K	0.999
19:35939848:C:G	N141K	0.999
19:35939907:T:C	L161P	0.999
19:35939921:A:T	N166Y	0.999
19:35939994:A:T	N190I	0.999
19:35939995:C:A	N190K	0.999
19:35939995:C:G	N190K	0.999
19:35940051:T:C	L209P	0.999

dbSNP variants (sampled 300 via entrez): RS1000165289 (19:35937428 G>C), RS1000372516 (19:35943048 C>T), RS1000427219 (19:35937201 A>G), RS1000743899 (19:35942856 C>T), RS1000828554 (19:35947039 G>A), RS1001078893 (19:35936915 C>T), RS1001232919 (19:35936481 C>T), RS1001348919 (19:35941434 A>T), RS1001431683 (19:35935604 T>G), RS1001531697 (19:35937337 C>G,T), RS1001580789 (19:35936179 C>T), RS1001780319 (19:35941678 T>C), RS1001847999 (19:35945736 G>A), RS1001879069 (19:35945972 G>A,T), RS1002978852 (19:35945568 C>G)

Disease associations

OMIM: gene MIM:612809 | 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

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression, increases expression	2
GSK-J4	decreases expression	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
cobaltous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Vanadium	increases abundance, increases methylation	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	increases expression	1
Metals, Heavy	increases abundance, increases methylation	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases expression	1
Vitamin K 3	affects expression	1

Clinical trials (associated diseases)

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