BTNL3

Summary

BTNL3 (butyrophilin like 3, HGNC:1143) is a protein-coding gene on chromosome 5q35.3, encoding Butyrophilin-like protein 3 (Q6UXE8).

Predicted to enable signaling receptor binding activity. Predicted to be involved in T cell receptor signaling pathway and regulation of cytokine production. Predicted to be located in membrane. Predicted to be active in external side of plasma membrane.

Source: NCBI Gene 10917 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 86 total
• MANE Select transcript: NM_197975

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1143
Approved symbol	BTNL3
Name	butyrophilin like 3
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Aliases	BTNLR, BTN9.1
Ensembl gene	ENSG00000168903
Ensembl biotype	protein_coding
OMIM	606192
Entrez	10917

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000342868, ENST00000899564, ENST00000946317

RefSeq mRNA: 1 — MANE Select: NM_197975 NM_197975

CCDS: CCDS47358

Canonical transcript exons

ENST00000342868 — 8 exons

Exon	Start	End
ENSE00001150064	181002672	181002785
ENSE00001150079	180992813	180993160
ENSE00002059720	180988846	180989077
ENSE00002087794	181005334	181006727
ENSE00002431722	181003856	181003876
ENSE00002448926	181004736	181004762
ENSE00002463282	181004417	181004443
ENSE00002477313	180997213	180997488

Expression profiles

Bgee: expression breadth ubiquitous, 128 present calls, max score 96.32.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3842 / max 235.1313, expressed in 13 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60667	0.1849	9
60671	0.1610	10
60669	0.0177	7
60668	0.0115	5
60670	0.0091	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	96.32	gold quality
ileal mucosa	UBERON:0000331	95.14	gold quality
mucosa of transverse colon	UBERON:0004991	94.18	gold quality
duodenum	UBERON:0002114	93.96	gold quality
type B pancreatic cell	CL:0000169	91.62	gold quality
olfactory bulb	UBERON:0002264	91.08	silver quality
colonic mucosa	UBERON:0000317	90.18	gold quality
rectum	UBERON:0001052	89.01	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.32	gold quality
pancreatic ductal cell	CL:0002079	86.54	gold quality
left ventricle myocardium	UBERON:0006566	86.31	silver quality
small intestine Peyer’s patch	UBERON:0003454	85.79	gold quality
small intestine	UBERON:0002108	85.29	gold quality
jejunum	UBERON:0002115	83.62	gold quality
diaphragm	UBERON:0001103	83.38	silver quality
transverse colon	UBERON:0001157	81.52	gold quality
epithelial cell of pancreas	CL:0000083	81.48	silver quality
triceps brachii	UBERON:0001509	79.32	gold quality
gluteal muscle	UBERON:0002000	78.49	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	78.37	gold quality
tibialis anterior	UBERON:0001385	78.12	silver quality
oocyte	CL:0000023	76.65	gold quality
periodontal ligament	UBERON:0008266	74.03	silver quality
deltoid	UBERON:0001476	73.96	silver quality
male germ cell	CL:0000015	73.89	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	73.89	gold quality
intestine	UBERON:0000160	73.82	gold quality
biceps brachii	UBERON:0001507	73.05	gold quality
superficial temporal artery	UBERON:0001614	72.82	gold quality
nasal cavity epithelium	UBERON:0005384	72.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.92

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

72 targeting BTNL3, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548A-5P	99.94	71.27	3482
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
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-374A-5P	99.90	71.34	2923

Literature-anchored findings (GeneRIF, showing 2)

• analysis of genomic information from multiple non-cancer cohorts showed that both the NEGR1 promoter deletion and the BTNL3-8 deletion were CNVs occurring at high frequencies in the general population. Intriguingly, the upstream NEGR1 CNV deletion was homozygous in ~ 40% of individuals in the non-cancer population. (PMID:32375678)
• Frameshift mutations of immunomodulatory BTN2A1, BTN2A2, and BTNL3 genes in colon cancers. (PMID:37634314)

Cross-species orthologs

0 orthologs

Paralogs (15): BTN3A1 (ENSG00000026950), CD276 (ENSG00000103855), BTN3A3 (ENSG00000111801), BTN2A1 (ENSG00000112763), BTNL8 (ENSG00000113303), HHLA2 (ENSG00000114455), BTN2A2 (ENSG00000124508), BTN1A1 (ENSG00000124557), VTCN1 (ENSG00000134258), ICOSLG (ENSG00000160223), ERMAP (ENSG00000164010), BTNL9 (ENSG00000165810), BTN3A2 (ENSG00000186470), BTNL2 (ENSG00000204290), MOG (ENSG00000204655)

Protein

Protein identifiers

Butyrophilin-like protein 3 — Q6UXE8 (reviewed: Q6UXE8)

Alternative names: Butyrophilin-like receptor

All UniProt accessions (1): Q6UXE8

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane.

Tissue specificity. Expressed in small intestine, colon, testis, spleen, and leukocyte.

Similarity. Belongs to the immunoglobulin superfamily. BTN/MOG family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6UXE8-1	1	yes
Q6UXE8-2	2

RefSeq proteins (1): NP_932079* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001870	B30.2/SPRY	Domain
IPR003599	Ig_sub	Domain
IPR003877	SPRY_dom	Domain
IPR003879	Butyrophylin_SPRY	Domain
IPR006574	PRY	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR043136	B30.2/SPRY_sf	Homologous_superfamily
IPR050504	IgSF_BTN/MOG-like	Family
IPR053896	BTN3A2-like_Ig-C	Domain

Pfam: PF00622, PF07686, PF13765, PF22705

UniProt features (10 total): topological domain 2, domain 2, splice variant 2, signal peptide 1, chain 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UXE8-F1	89.50	0.68

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 51 (showing top): GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, GOBP_REGULATION_OF_IMMUNE_RESPONSE, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_CYTOKINE_PRODUCTION, GOBP_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOMF_SIGNALING_RECEPTOR_BINDING, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_UP, GOBP_T_CELL_SELECTION, SHEN_SMARCA2_TARGETS_DN, GOCC_SIDE_OF_MEMBRANE, GOBP_T_CELL_DIFFERENTIATION, GOBP_LYMPHOCYTE_DIFFERENTIATION, DITTMER_PTHLH_TARGETS_DN, MOREAUX_MULTIPLE_MYELOMA_BY_TACI_UP

GO Biological Process (4): regulation of cytokine production (GO:0001817), extrathymic T cell selection (GO:0045062), T cell receptor signaling pathway (GO:0050852), biological_process (GO:0008150)

GO Molecular Function (3): signaling receptor binding (GO:0005102), molecular_function (GO:0003674), protein binding (GO:0005515)

GO Cellular Component (3): external side of plasma membrane (GO:0009897), cellular_component (GO:0005575), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytokine production	1
regulation of gene expression	1
regulation of multicellular organismal process	1
extrathymic T cell differentiation	1
T cell selection	1
antigen receptor-mediated signaling pathway	1
protein binding	1
binding	1
plasma membrane	1
cell surface	1
side of membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

476 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BTNL3	XDH	P47989	969
BTNL3	PLIN2	Q99541	922
BTNL3	MFGE8	Q08431	783
BTNL3	CASD1	Q96PB1	600
BTNL3	MUC1	P13931	597
BTNL3	LTF	P02788	591
BTNL3	GOT2	P00505	550
BTNL3	MUC15	Q8N387	517
BTNL3	CIDEA	O60543	513
BTNL3	OMG	P23515	491
BTNL3	AASDH	Q4L235	471
BTNL3	LALBA	P00709	447
BTNL3	PLIN1	O60240	443
BTNL3	HLA-A	P01891	437
BTNL3	HLA-DRB1	P01911	424

IntAct

7 interactions, top by confidence:

A	B	Type	Score
BTNL3	FAM171A2	psi-mi:“MI:0914”(association)	0.530
BTNL8	BTNL3	psi-mi:“MI:0915”(physical association)	0.400
RNF44	BTNL3	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (33): ITGA5 (Affinity Capture-MS), SLC25A51 (Affinity Capture-MS), CYP20A1 (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS), FAM171A2 (Affinity Capture-MS), SCARB1 (Affinity Capture-MS), EEF1A2 (Affinity Capture-MS), ACP2 (Affinity Capture-MS), CYP20A1 (Affinity Capture-MS), ATF6B (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), ITGA6 (Affinity Capture-MS), ECEL1 (Affinity Capture-MS), CYB5R1 (Affinity Capture-MS), FNDC3A (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4J1G0, A0A0B4J1L0, A0A0G2KBC9, A1YIY0, A8MTB9, B6A8R8, C0HJX2, C0HJX3, E2RP87, H0VDZ8, P08637, P09326, P12314, P23505, P26151, P43626, P43627, P43628, P43631, P43632, P83555, P83556, Q01965, Q13291, Q14952, Q14953, Q14954, Q28942, Q2YHT5, Q61400, Q61450, Q640U3, Q68EV1, Q68SN8, Q6UX41, Q6UXE8, Q6UY09, Q6XJV4, Q6XPU4, Q7TST0

Diamond homologs: A0A0E4BZH1, A4QPC6, A7TZE6, A7TZF0, A7TZF3, A7TZG1, A7TZG3, A7XUX6, A7XUY5, A7XUZ6, A7XV04, A7XV07, A7XV14, A8MVZ5, O00478, O00481, O70355, P18892, P55803, P78410, Q13410, Q16653, Q29ZQ1, Q5R7W8, Q5R960, Q5R996, Q61885, Q62556, Q63345, Q6MG97, Q6UX41, Q6UXE8, Q6UXG8, Q7KYR7, Q7TST0, Q8BJE2, Q8WVV5, Q96KV6, Q96PL5, Q9BGS7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	69
Likely benign	8
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1202 predictions. Top by Δscore:

Variant	Effect	Δscore
5:181003976:G:GT	donor_gain	1.0000
5:181003996:G:T	donor_gain	1.0000
5:181004415:A:AG	acceptor_gain	1.0000
5:181004416:G:GG	acceptor_gain	1.0000
5:181003996:G:GT	donor_gain	0.9900
5:181004025:GCTCA:G	donor_gain	0.9900
5:181004055:GGCT:G	donor_gain	0.9900
5:181004080:G:GT	donor_gain	0.9900
5:181004407:T:A	acceptor_gain	0.9900
5:181004415:AGACT:A	acceptor_gain	0.9900
5:181004416:G:GA	acceptor_loss	0.9900
5:181004416:GA:G	acceptor_gain	0.9900
5:181004416:GACT:G	acceptor_gain	0.9900
5:181004416:GACTG:G	acceptor_gain	0.9900
5:181005322:A:AG	acceptor_gain	0.9900
5:181005322:ACC:A	acceptor_gain	0.9900
5:181005323:C:G	acceptor_gain	0.9900
5:181005324:C:CA	acceptor_gain	0.9900
5:181005327:A:AG	acceptor_gain	0.9900
5:180993011:G:GT	donor_gain	0.9800
5:180997366:A:G	donor_gain	0.9800
5:181002671:GAGAC:G	acceptor_gain	0.9800
5:181003986:C:T	donor_gain	0.9800
5:181004029:A:AG	donor_gain	0.9800
5:181004029:A:G	donor_gain	0.9800
5:181004034:T:G	donor_gain	0.9800
5:181004062:GA:G	donor_gain	0.9800
5:181005332:A:AG	acceptor_gain	0.9800
5:181005333:G:GG	acceptor_gain	0.9800
5:180992974:G:GT	donor_gain	0.9700

AlphaMissense

3040 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:180992926:T:C	F55L	0.979
5:180992928:C:A	F55L	0.979
5:180992928:C:G	F55L	0.979
5:181005444:T:C	F325L	0.970
5:181005446:T:A	F325L	0.970
5:181005446:T:G	F325L	0.970
5:180997275:T:A	C154S	0.964
5:180997276:G:C	C154S	0.964
5:180993103:T:A	C114S	0.963
5:180993104:G:C	C114S	0.963
5:180997314:T:A	W167R	0.963
5:180997314:T:C	W167R	0.963
5:180997316:G:C	W167C	0.961
5:180997316:G:T	W167C	0.961
5:181005477:T:C	F336L	0.960
5:181005479:C:A	F336L	0.960
5:181005479:C:G	F336L	0.960
5:180992929:T:C	F56L	0.955
5:180992931:C:A	F56L	0.955
5:180992931:C:G	F56L	0.955
5:180992876:T:C	F38S	0.954
5:180992924:G:C	R54P	0.954
5:180997292:G:C	W159C	0.952
5:180997292:G:T	W159C	0.952
5:181005498:T:A	W343R	0.952
5:181005498:T:C	W343R	0.952
5:180993059:T:C	L99P	0.951
5:180992927:T:C	F55S	0.949
5:180997277:C:G	C154W	0.949
5:181005500:G:C	W343C	0.948

dbSNP variants (sampled 300 via entrez): RS1000208551 (5:180987725 C>G), RS1000254824 (5:181003098 G>A), RS1000360653 (5:180995847 G>A), RS1000861700 (5:181001372 T>C), RS1000964057 (5:181007112 A>C,G), RS1001005689 (5:181001405 G>T), RS1001041359 (5:180994761 G>T), RS1001338547 (5:180989283 G>A), RS1001367226 (5:180993950 G>A), RS1001584890 (5:180999627 C>T), RS1001923198 (5:180991515 G>A), RS1002268179 (5:180999949 A>G), RS1002310537 (5:180994196 C>T), RS1002869721 (5:180998197 T>C), RS1002929968 (5:180989774 C>T)

Disease associations

OMIM: gene MIM:606192 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005166_12	GIP levels in response to oral glucose tolerance test (120 minutes)	3.000000e-06
GCST010241_57	Apolipoprotein A1 levels	1.000000e-14
GCST010242_346	HDL cholesterol levels	1.000000e-12

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004307	glucose tolerance test
EFO:0008464	glucose-dependent insulinotropic peptide measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Butyrophilin and butyrophilin-like proteins

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Malathion	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Aflatoxin B1	increases methylation	1
Permethrin	increases expression	1

Clinical trials (associated diseases)

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