BRI3

Summary

BRI3 (brain protein I3, HGNC:1109) is a protein-coding gene on chromosome 7q21.3, encoding Membrane protein BRI3 (O95415). Participates in tumor necrosis factor-alpha (TNF)-induced cell death. It is a selective cancer dependency (DepMap: 12.5% of cell lines).

Enables identical protein binding activity. Predicted to be located in azurophil granule membrane and plasma membrane.

Source: NCBI Gene 25798 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 34 total
• Cancer dependency (DepMap): dependent in 12.5% of screened cell lines
• MANE Select transcript: NM_015379

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1109
Approved symbol	BRI3
Name	brain protein I3
Location	7q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000164713
Ensembl biotype	protein_coding
OMIM	615628
Entrez	25798

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding_CDS_not_defined, 2 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000297290, ENST00000456357, ENST00000473967, ENST00000474291, ENST00000485422, ENST00000491463, ENST00000539286

RefSeq mRNA: 2 — MANE Select: NM_015379 NM_001159491, NM_015379

CCDS: CCDS55133, CCDS5656

Canonical transcript exons

ENST00000297290 — 3 exons

Exon	Start	End
ENSE00001182785	98281686	98281937
ENSE00003528069	98291111	98291545
ENSE00003551499	98282351	98282453

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 99.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 151.0636 / max 1710.6031, expressed in 1823 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79822	108.7144	1820
79823	15.9712	1745
79821	15.2244	1802
79814	3.6247	1509
79819	2.3304	1409
79824	2.0115	1078
79820	1.5892	1238
79827	1.2112	677
79826	0.2947	152
79825	0.0919	29

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	99.22	gold quality
ileal mucosa	UBERON:0000331	99.14	gold quality
upper lobe of left lung	UBERON:0008952	99.08	gold quality
upper lobe of lung	UBERON:0008948	99.06	gold quality
kidney epithelium	UBERON:0004819	99.03	gold quality
body of stomach	UBERON:0001161	98.98	gold quality
left adrenal gland cortex	UBERON:0035825	98.97	gold quality
right adrenal gland	UBERON:0001233	98.94	gold quality
right adrenal gland cortex	UBERON:0035827	98.94	gold quality
left adrenal gland	UBERON:0001234	98.92	gold quality
left ventricle myocardium	UBERON:0006566	98.91	gold quality
leukocyte	CL:0000738	98.89	gold quality
monocyte	CL:0000576	98.88	gold quality
body of pancreas	UBERON:0001150	98.87	gold quality
tibialis anterior	UBERON:0001385	98.86	gold quality
decidua	UBERON:0002450	98.83	gold quality
adrenal cortex	UBERON:0001235	98.78	gold quality
right coronary artery	UBERON:0001625	98.76	gold quality
apex of heart	UBERON:0002098	98.70	gold quality
lower lobe of lung	UBERON:0008949	98.70	gold quality
granulocyte	CL:0000094	98.67	gold quality
gastrocnemius	UBERON:0001388	98.67	gold quality
ascending aorta	UBERON:0001496	98.63	gold quality
thoracic aorta	UBERON:0001515	98.63	gold quality
left coronary artery	UBERON:0001626	98.61	gold quality
omental fat pad	UBERON:0010414	98.60	gold quality
peritoneum	UBERON:0002358	98.54	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.54	gold quality
mucosa of stomach	UBERON:0001199	98.53	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.53	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-8530	yes	2528.98
E-HCAD-13	yes	1989.34
E-MTAB-8271	yes	668.74
E-HCAD-1	yes	82.60
E-CURD-122	yes	66.92
E-MTAB-6701	yes	46.93
E-GEOD-135922	yes	41.40
E-MTAB-9221	yes	27.68
E-ANND-3	yes	22.31
E-CURD-88	yes	11.16
E-CURD-97	no	75.10

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

36 targeting BRI3, 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-3613-3P	100.00	76.36	7965
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-6838-3P	98.40	65.88	559
HSA-MIR-6784-3P	98.39	64.88	662

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 12.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

• An X-ray data set was collected to 1.6 A resolution using synchrotron radiation, of a ligandin recombinant fusion protein. (PMID:16508092)
• BRI3 RNA is expressed less in stage 3 colon cancer in comparison to stage 2 colon cancer, and it is among 8 genes which can be used as a gene signature to differentiate colon cancer stages. (PMID:17390049)
• Possible roles of BRI3 in the process of neuronal differentiation. (PMID:18452648)
• BRI3 inhibits the various processing of amyloid protein precursor by blocking the access of alpha- and beta-secretases. (PMID:19366692)
• In the context of hepatocellular carcinoma cells, BRI3 is a target of WNT signaling. (PMID:20538055)
• NRBP1-Containing CRL2/CRL4A Regulates Amyloid beta Production by Targeting BRI2 and BRI3 for Degradation. (PMID:32160551)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	bri3	ENSDARG00000086332
mus_musculus	Bri3	ENSMUSG00000047843
rattus_norvegicus	Bri3	ENSRNOG00000001009
drosophila_melanogaster	CG12012	FBGN0035444
caenorhabditis_elegans		WBGENE00017385

Protein

Protein identifiers

Membrane protein BRI3 — O95415 (reviewed: O95415)

Alternative names: Brain protein I3, pRGR2

All UniProt accessions (2): O95415, I3L1V6

UniProt curated annotations — full annotation on UniProt →

Function. Participates in tumor necrosis factor-alpha (TNF)-induced cell death. May be a target of Wnt/beta-catenin signaling in the liver.

Subunit / interactions. Interacts with BRI3BP. Interacts with MGAT1 and IFITM3. Interacts with BRI3BP, MGAT1 and IFITM3; the interactions are weaker than with isoform 1.

Subcellular location. Lysosome membrane Cytoplasm. Perinuclear region Cytoplasm. Nucleus.

Induction. Up-regulated during TNF-mediated inflammation and immunity. Up-regulated by beta-catenin and TCF4.

Similarity. Belongs to the BRI3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O95415-1	1, a	yes
O95415-2	2, b

RefSeq proteins (2): NP_001152963, NP_056194* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019317	BRI3	Family

Pfam: PF10164

UniProt features (7 total): transmembrane region 2, splice variant 2, chain 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95415-F1	65.20	0.03

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 148 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, UEDA_PERIFERAL_CLOCK, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, TGAGATT_MIR216, GOCC_SECRETORY_VESICLE, GOCC_SECRETORY_GRANULE_MEMBRANE, TTTGCAG_MIR518A2, JOHNSTONE_PARVB_TARGETS_3_UP, GOCC_AZUROPHIL_GRANULE_MEMBRANE, GOCC_AZUROPHIL_GRANULE, REACTOME_NEUTROPHIL_DEGRANULATION, BANP_TARGET_GENES

GO Biological Process (0):

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), plasma membrane (GO:0005886), azurophil granule membrane (GO:0035577), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), lysosome (GO:0005764), lysosomal membrane (GO:0005765), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
lysosomal membrane	1
secretory granule membrane	1
azurophil granule	1
cytoplasm	1
intracellular anatomical structure	1
lytic vacuole	1
lysosome	1
lytic vacuole membrane	1

Protein interactions and networks

STRING

164 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BRI3	OR6A2	O95222	766
BRI3	PPP1R2C	O14990	624
BRI3	TPPP	O94811	333
BRI3	HR	O43593	325
BRI3	GDF11	O95390	306
BRI3	ARHGEF15	O94989	299
BRI3	CDIN1	Q9Y2V0	290
BRI3	MYRF	Q9Y2G1	280
BRI3	HIC2	Q96JB3	254
BRI3	ACKR5	O15218	248
BRI3	ARL6IP4	Q66PJ3	245
BRI3	EEF2K	O00418	239
BRI3	HDAC7	Q8WUI4	238
BRI3	ADH1A	P07327	231
BRI3	NXT2	Q9NPJ8	224
BRI3	PCSK5	Q92824	224

IntAct

37 interactions, top by confidence:

A	B	Type	Score
BRI3	BRI3BP	psi-mi:“MI:0915”(physical association)	0.570
BRI3	MALL	psi-mi:“MI:0915”(physical association)	0.560
BRI3	ABHD16A	psi-mi:“MI:0915”(physical association)	0.560
BRI3	IFITM3	psi-mi:“MI:0915”(physical association)	0.540
BRI3	MGAT1	psi-mi:“MI:0915”(physical association)	0.540
BRI3	IFITM3	psi-mi:“MI:0403”(colocalization)	0.540
BRI3	MGAT1	psi-mi:“MI:0403”(colocalization)	0.540
MGAT1	BRI3	psi-mi:“MI:0915”(physical association)	0.540
GPRC5B	STXBP3	psi-mi:“MI:0914”(association)	0.530
KCNK16	B3GAT3	psi-mi:“MI:0914”(association)	0.530
PRRT2	NDUFS4	psi-mi:“MI:0914”(association)	0.530
SLC30A2	ESYT2	psi-mi:“MI:0914”(association)	0.530
TMEM43	ENDOD1	psi-mi:“MI:0914”(association)	0.530
BRI3	IL7R	psi-mi:“MI:0915”(physical association)	0.370
ACKR3	PDE2A	psi-mi:“MI:0914”(association)	0.350
CCR9	ABCC4	psi-mi:“MI:0914”(association)	0.350
CXCR3	RIMOC1	psi-mi:“MI:0914”(association)	0.350
CXCR4	ESYT2	psi-mi:“MI:0914”(association)	0.350
DLK1	PLPP3	psi-mi:“MI:0914”(association)	0.350
HTR1E	ESYT2	psi-mi:“MI:0914”(association)	0.350
SPPL2B	POC1B-GALNT4	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): BRI3 (Two-hybrid), ABHD16A (Two-hybrid), BRI3 (Affinity Capture-RNA), BRI3 (Affinity Capture-MS), BRI3 (Affinity Capture-MS), BRI3 (Affinity Capture-RNA), BRI3 (Two-hybrid), BRI3 (Affinity Capture-Western), BRI3 (Affinity Capture-Western), Bace1 (Affinity Capture-Western)

ESM2 similar proteins: B6SGC5, O95415, P0C0T0, P28662, P50636, Q32L83, Q3C2P8, Q3T0A9, Q3TWL2, Q4R5H7, Q4R6W2, Q58D45, Q5BJ83, Q5E9E8, Q5EAU3, Q5F3S2, Q5PPK1, Q5PPM8, Q5PQS5, Q5R4K6, Q5RDN2, Q5U2U6, Q5XID0, Q5XKA6, Q5Y171, Q66I51, Q66JG9, Q6DC04, Q6DIE4, Q6GMG8, Q6NYG4, Q6NYK3, Q6P828, Q7Z698, Q7Z699, Q86T03, Q8AVW3, Q8N114, Q8QGW7, Q8VIH7

Diamond homologs: O95415, P28662, Q32L83, Q5PPK1, Q99N46

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 30 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
G alpha (i) signalling events	5	9.3×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
immune response	6	10.5×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	19
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1422 predictions. Top by Δscore:

Variant	Effect	Δscore
7:98281933:CACAG:C	donor_loss	1.0000
7:98281934:ACAGG:A	donor_loss	1.0000
7:98281938:G:GA	donor_loss	1.0000
7:98282348:CA:C	acceptor_loss	1.0000
7:98282349:A:AC	acceptor_loss	1.0000
7:98282349:A:AG	acceptor_gain	1.0000
7:98282349:AG:A	acceptor_gain	1.0000
7:98282349:AGG:A	acceptor_gain	1.0000
7:98282350:G:GT	acceptor_gain	1.0000
7:98282350:GG:G	acceptor_gain	1.0000
7:98282350:GGG:G	acceptor_gain	1.0000
7:98282350:GGGA:G	acceptor_gain	1.0000
7:98282350:GGGAT:G	acceptor_gain	1.0000
7:98282451:CAGGT:C	donor_loss	1.0000
7:98282453:GGT:G	donor_loss	1.0000
7:98282454:GTGA:G	donor_loss	1.0000
7:98282455:T:A	donor_loss	1.0000
7:98293592:CTCCG:C	acceptor_gain	1.0000
7:98293593:TCCG:T	acceptor_gain	1.0000
7:98293594:CCG:C	acceptor_gain	1.0000
7:98293594:CCGC:C	acceptor_gain	1.0000
7:98293595:CG:C	acceptor_gain	1.0000
7:98293595:CGC:C	acceptor_gain	1.0000
7:98293597:C:CC	acceptor_gain	1.0000
7:98304379:C:CT	acceptor_gain	1.0000
7:98304385:C:CT	acceptor_gain	1.0000
7:98304386:A:T	acceptor_gain	1.0000
7:98307682:GACTT:G	donor_loss	1.0000
7:98307683:ACTT:A	donor_loss	1.0000
7:98307684:CTT:C	donor_loss	1.0000

AlphaMissense

798 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:98282440:T:A	C78S	1.000
7:98282440:T:C	C78R	1.000
7:98282441:G:A	C78Y	1.000
7:98282441:G:C	C78S	1.000
7:98282442:T:G	C78W	1.000
7:98282449:T:C	C81R	1.000
7:98282450:G:A	C81Y	1.000
7:98282453:G:T	R82M	1.000
7:98291115:G:A	G84R	1.000
7:98291115:G:C	G84R	1.000
7:98291115:G:T	G84W	1.000
7:98291116:G:A	G84E	1.000
7:98291116:G:T	G84V	1.000
7:98291145:G:C	G94R	1.000
7:98291146:G:A	G94D	1.000
7:98291146:G:T	G94V	1.000
7:98291173:C:A	P103H	1.000
7:98291178:G:A	G105R	1.000
7:98291178:G:C	G105R	1.000
7:98291178:G:T	G105W	1.000
7:98291179:G:A	G105E	1.000
7:98291179:G:T	G105V	1.000
7:98291214:T:A	C117S	1.000
7:98291214:T:C	C117R	1.000
7:98291215:G:C	C117S	1.000
7:98291223:T:A	C120S	1.000
7:98291223:T:C	C120R	1.000
7:98291224:G:A	C120Y	1.000
7:98291224:G:C	C120S	1.000
7:98291224:G:T	C120F	1.000

dbSNP variants (sampled 300 via entrez): RS1000003091 (7:98288366 G>A,T), RS1000013887 (7:98300929 C>T), RS1000079497 (7:98306360 A>G), RS1000184702 (7:98317164 A>T), RS1000255250 (7:98301148 T>A,C), RS1000280857 (7:98281624 G>A,T), RS1000361155 (7:98290580 C>G,T), RS1000368844 (7:98302804 T>TA), RS1000374703 (7:98281701 A>C,T), RS1000436161 (7:98308471 G>A), RS1000443002 (7:98281349 G>A,C), RS1000494707 (7:98321534 G>A), RS1000546831 (7:98321834 C>A,G,T), RS1000565224 (7:98315686 G>A), RS1000608849 (7:98287397 G>A)

Disease associations

OMIM: gene MIM:615628 | 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
GCST90002389_159	Lymphocyte percentage of white cells	3.000000e-20
GCST90002393_68	Monocyte count	2.000000e-13
GCST90002399_183	Neutrophil percentage of white cells	7.000000e-15

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0005091	monocyte count
EFO:0007990	neutrophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
Estradiol	increases expression, decreases expression, affects cotreatment	2
GSK-J4	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
lead acetate	increases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	increases methylation	1
jinfukang	increases expression	1
(+)-JQ1 compound	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	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	affects methylation	1
Coumestrol	decreases expression	1
Diazinon	increases methylation	1
Diuron	decreases expression	1
Doxorubicin	increases expression	1
Fluoxetine	increases expression	1
Methapyrilene	increases methylation	1
Methyl Methanesulfonate	increases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Tretinoin	increases expression	1
Metribolone	affects splicing	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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