BFAR

Summary

BFAR (bifunctional apoptosis regulator, HGNC:17613) is a protein-coding gene on chromosome 16p13.12, encoding Bifunctional apoptosis regulator (Q9NZS9). Membrane-bound E3 ubiquitin ligase that plays a role in several processes including apoptosis regulation or reticulum endoplasmic stress.

Enables caspase binding activity; protein-macromolecule adaptor activity; and ubiquitin protein ligase activity. Involved in negative regulation of IRE1-mediated unfolded protein response; proteasome-mediated ubiquitin-dependent protein catabolic process; and protein ubiquitination. Acts upstream of or within negative regulation of apoptotic process. Located in endoplasmic reticulum and membrane.

Source: NCBI Gene 51283 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 78 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_016561

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17613
Approved symbol	BFAR
Name	bifunctional apoptosis regulator
Location	16p13.12
Locus type	gene with protein product
Status	Approved
Aliases	BAR, RNF47
Ensembl gene	ENSG00000103429
Ensembl biotype	protein_coding
OMIM	619516
Entrez	51283

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 16 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000261658, ENST00000562121, ENST00000562442, ENST00000562545, ENST00000563082, ENST00000563313, ENST00000563971, ENST00000564078, ENST00000565478, ENST00000566520, ENST00000566710, ENST00000570219, ENST00000901099, ENST00000901100, ENST00000901101, ENST00000901102, ENST00000911310, ENST00000911311, ENST00000911312, ENST00000911313, ENST00000955228

RefSeq mRNA: 2 — MANE Select: NM_016561 NM_001330500, NM_016561

CCDS: CCDS10554, CCDS81947

Canonical transcript exons

ENST00000261658 — 8 exons

Exon	Start	End
ENSE00001942120	14667635	14669236
ENSE00001953121	14632951	14633018
ENSE00003460996	14648388	14648592
ENSE00003563321	14661892	14662065
ENSE00003607781	14649804	14649973
ENSE00003646355	14644274	14644609
ENSE00003648143	14655066	14655210
ENSE00003659842	14664869	14665071

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 95.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 59.8634 / max 531.8351, expressed in 1819 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152877	57.8467	1819
152878	2.0166	1309

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	95.26	gold quality
right lung	UBERON:0002167	94.98	gold quality
pancreas	UBERON:0001264	94.54	gold quality
rectum	UBERON:0001052	94.36	gold quality
body of pancreas	UBERON:0001150	94.34	gold quality
smooth muscle tissue	UBERON:0001135	93.87	gold quality
gall bladder	UBERON:0002110	93.86	gold quality
adrenal tissue	UBERON:0018303	93.41	gold quality
placenta	UBERON:0001987	93.34	gold quality
upper lobe of left lung	UBERON:0008952	93.34	gold quality
lung	UBERON:0002048	93.24	gold quality
stromal cell of endometrium	CL:0002255	93.23	gold quality
duodenum	UBERON:0002114	93.11	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.10	gold quality
subcutaneous adipose tissue	UBERON:0002190	92.99	gold quality
muscle tissue	UBERON:0002385	92.92	gold quality
gastrocnemius	UBERON:0001388	92.83	gold quality
muscle of leg	UBERON:0001383	92.71	gold quality
skeletal muscle organ	UBERON:0014892	92.71	gold quality
embryo	UBERON:0000922	92.69	gold quality
ganglionic eminence	UBERON:0004023	92.69	gold quality
skeletal muscle tissue	UBERON:0001134	92.67	gold quality
colonic epithelium	UBERON:0000397	92.62	gold quality
endometrium	UBERON:0001295	92.58	gold quality
adipose tissue	UBERON:0001013	92.56	gold quality
popliteal artery	UBERON:0002250	92.39	gold quality
tibial artery	UBERON:0007610	92.39	gold quality
leukocyte	CL:0000738	92.24	gold quality
monocyte	CL:0000576	92.21	gold quality
cortical plate	UBERON:0005343	92.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.02

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

66 targeting BFAR, 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-4533	100.00	69.48	2758
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4282	99.99	75.36	6408
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-587	99.64	70.86	2611

Literature-anchored findings (GeneRIF, showing 5)

• Over-expression of BFAR Delta RING renders the heart more resistant to I/R injury and DOX-induced cardiotoxicity, and this protection correlates with reduced cardiomyocyte apoptosis. (PMID:18805781)
• post-translational regulation of the BI-1 protein by E3 ligase BAR contributes to the dynamic control of IRE1 signaling during endoplasmic reticulum stress (PMID:21068390)
• Data show that p75NTR and BFAR co-localized within the cytoplasm. (PMID:22566094)
• BFAR coordinates TGFbeta signaling to modulate Th9-mediated cancer immunotherapy. (PMID:33914044)
• The periphilin 1-like BFAR isoform 3 is highly expressed in transcriptionally silent oocytes and involved in RNA metabolism. (PMID:34175335)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Bfar	ENSMUSG00000022684
rattus_norvegicus	Bfar	ENSRNOG00000003151

Protein

Protein identifiers

Bifunctional apoptosis regulator — Q9NZS9 (reviewed: Q9NZS9)

Alternative names: RING finger protein 47

All UniProt accessions (9): A0A087WXR3, Q9NZS9, H3BMP2, H3BMY8, H3BPQ8, H3BRQ5, H3BSU2, H3BTG6, H3BUB3

UniProt curated annotations — full annotation on UniProt →

Function. Membrane-bound E3 ubiquitin ligase that plays a role in several processes including apoptosis regulation or reticulum endoplasmic stress. Has anti-apoptotic activity, both for apoptosis triggered via death-receptors and via mitochondrial factors. Contributes to the dynamic control of IRE1/ERN1 signaling during ER stress by inducing BAX inhibitor 1/TMBIM6 proteasomal degradation. Promotes the activation of TGF-beta signaling by mediating the ‘Lys-63’-linked ubiquitination of TGFBR1 which is critical to activate the pathway. Together with NGFR, negatively regulates NF-kappa-B and JNK-related signaling pathways. Promotes the proteasome-mediated degradation of PNPLA3, a protein involveld in lipid metabolism.

Subunit / interactions. Interacts with CASP8, BCL2 and BCL2L1 through SAM domain and also with HIP1, IFT57, ESRRBL1 and BCAP31. Interacts with NGFR; this interaction inhibits NF-kappa-B and JNK-related signaling pathways.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed highly in brain, moderately in small intestine, weakly in testes and only faintly in liver and skeletal muscle. Not expressed in heart, kidney, lung and spleen.

Post-translational modifications. Mediates RING-dependent self-ubiquitination leading to proteasomal degradation.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NZS9-1	1	yes
Q9NZS9-2	2

RefSeq proteins (2): NP_001317429, NP_057645* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001660	SAM	Domain
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site

Pfam: PF00536, PF15227

UniProt features (18 total): topological domain 5, transmembrane region 4, splice variant 2, sequence variant 2, chain 1, domain 1, zinc finger region 1, region of interest 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZS9-F1	82.40	0.41

Functional residue map

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

Glycosylation sites (1): 232

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 163 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_IRE1_MEDIATED_UNFOLDED_PROTEIN_RESPONSE, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_IRE1_MEDIATED_UNFOLDED_PROTEIN_RESPONSE, FOSTER_TOLERANT_MACROPHAGE_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_PROTEIN_AUTOUBIQUITINATION, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GGCKCATGS_UNKNOWN, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION

GO Biological Process (10): protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), apoptotic process (GO:0006915), negative regulation of apoptotic process (GO:0043066), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), protein autoubiquitination (GO:0051865), protein K63-linked ubiquitination (GO:0070534), protein K48-linked ubiquitination (GO:0070936), negative regulation of IRE1-mediated unfolded protein response (GO:1903895), IRE1-mediated unfolded protein response (GO:0036498)

GO Molecular Function (7): zinc ion binding (GO:0008270), protein-macromolecule adaptor activity (GO:0030674), ubiquitin protein ligase activity (GO:0061630), caspase binding (GO:0089720), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	3
protein polyubiquitination	2
modification-dependent protein catabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
IRE1-mediated unfolded protein response	1
negative regulation of endoplasmic reticulum unfolded protein response	1
regulation of IRE1-mediated unfolded protein response	1
endoplasmic reticulum unfolded protein response	1
transition metal ion binding	1
protein binding	1
molecular adaptor activity	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
protease binding	1
binding	1
catalytic activity	1
cation binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

606 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BFAR	PDXDC1	Q6P996	915
BFAR	NOMO1	P78421	799
BFAR	ZC3H12A	Q5D1E8	762
BFAR	LTBR	P36941	616
BFAR	BCL2	P10415	503
BFAR	TNFRSF1B	P20333	494
BFAR	CAAP1	Q9H8G2	450
BFAR	CRADD	P78560	445
BFAR	TMBIM6	P55061	434
BFAR	NOL3	O60936	413
BFAR	BIRC6	Q9NR09	402
BFAR	BID	P55957	393
BFAR	CASP3	P42574	391
BFAR	CALCR	P30988	381
BFAR	CIDEB	Q9UHD4	379

IntAct

21 interactions, top by confidence:

A	B	Type	Score
UBE2K	BFAR	psi-mi:“MI:0915”(physical association)	0.720
BFAR	UBE2K	psi-mi:“MI:0915”(physical association)	0.720
BFAR	UBE2D1	psi-mi:“MI:0915”(physical association)	0.490
UBE2D2	BFAR	psi-mi:“MI:0915”(physical association)	0.490
UBE2D3	BFAR	psi-mi:“MI:0915”(physical association)	0.490
BFAR	UBE2W	psi-mi:“MI:0915”(physical association)	0.490
BFAR	UBE2U	psi-mi:“MI:0915”(physical association)	0.370
BFAR	UBE2N	psi-mi:“MI:0915”(physical association)	0.370
HIP2	BFAR	psi-mi:“MI:0915”(physical association)	0.370
UBE2D4	BFAR	psi-mi:“MI:0915”(physical association)	0.370
BFAR	PHYKPL	psi-mi:“MI:0914”(association)	0.350
UBE2K	BFAR	psi-mi:“MI:0915”(physical association)	0.000
sucA	BFAR	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (61): BFAR (Two-hybrid), BFAR (Affinity Capture-RNA), BFAR (Two-hybrid), BFAR (Proximity Label-MS), BFAR (Proximity Label-MS), BFAR (Positive Genetic), NDUFS2 (Affinity Capture-MS), ATPIF1 (Affinity Capture-MS), TYMS (Affinity Capture-MS), ALDH9A1 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), VAMP7 (Affinity Capture-MS), TMED1 (Affinity Capture-MS), PHYKPL (Affinity Capture-MS), SERGEF (Affinity Capture-MS)

ESM2 similar proteins: A0A0F7YYX3, A1Z0Q5, E1BRC3, E2AX35, E9PVB5, F5HFJ7, O76061, O88452, O97561, P03172, P06476, P09259, P09728, P22484, P24872, P28967, P28981, P32514, P33802, P36318, P55082, P57083, P68327, P84393, P85831, Q05059, Q2YDM0, Q3TBN1, Q499E0, Q4R6V5, Q5BKX0, Q5PQN2, Q5R9E4, Q5RDR5, Q69091, Q69467, Q6AY76, Q6AYF7, Q6DLD9, Q6NVG5

Diamond homologs: A0A3B3IT33, A6NCK2, A6NDI0, A6NGJ6, A6NI03, A6NLI5, B0BLU1, C9J1S8, I1YAP6, O00478, O00481, O15344, O75677, O75678, O75679, O76064, P0CI25, P0CI26, P18892, P19474, P62603, P86448, P86449, Q13410, Q2HJ46, Q3C1V9, Q3TL54, Q4KLN8, Q5EBN2, Q5PQN2, Q5R4I2, Q5R996, Q61510, Q62556, Q6INS5, Q6MFY8, Q6UX41, Q6UXE8, Q6ZWI9, Q7T308

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
BFAR	down-regulates	CASP8	binding
Ub:E2	“up-regulates activity”	BFAR	ubiquitination
BFAR	“down-regulates quantity by destabilization”	TMBIM6	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	64
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
58701	GRCh38/hg38 16p13.13-13.11(chr16:11967831-15162888)x1	Pathogenic
148522	GRCh38/hg38 16p13.13-13.11(chr16:11952467-15186199)x1	Likely pathogenic

SpliceAI

1466 predictions. Top by Δscore:

Variant	Effect	Δscore
16:14648382:CCATA:C	acceptor_loss	1.0000
16:14648383:CATA:C	acceptor_loss	1.0000
16:14648384:ATAG:A	acceptor_gain	1.0000
16:14648384:ATAGG:A	acceptor_gain	1.0000
16:14648385:TA:T	acceptor_loss	1.0000
16:14648386:A:AG	acceptor_gain	1.0000
16:14648386:AG:A	acceptor_gain	1.0000
16:14648386:AGG:A	acceptor_gain	1.0000
16:14648386:AGGG:A	acceptor_loss	1.0000
16:14648387:G:GG	acceptor_gain	1.0000
16:14648387:G:GT	acceptor_loss	1.0000
16:14648387:GG:G	acceptor_gain	1.0000
16:14648387:GGG:G	acceptor_gain	1.0000
16:14648387:GGGAT:G	acceptor_gain	1.0000
16:14648589:GGCA:G	donor_gain	1.0000
16:14648590:GCA:G	donor_gain	1.0000
16:14648590:GCAG:G	donor_gain	1.0000
16:14648593:G:GG	donor_gain	1.0000
16:14655065:GGTT:G	acceptor_gain	1.0000
16:14655202:GAATA:G	donor_gain	1.0000
16:14661887:T:TA	acceptor_gain	1.0000
16:14661887:TGCA:T	acceptor_loss	1.0000
16:14661888:GCA:G	acceptor_loss	1.0000
16:14661890:A:AG	acceptor_gain	1.0000
16:14661890:A:C	acceptor_loss	1.0000
16:14661890:AG:A	acceptor_gain	1.0000
16:14661890:AGGCT:A	acceptor_gain	1.0000
16:14661891:G:A	acceptor_loss	1.0000
16:14661891:G:GG	acceptor_gain	1.0000
16:14661891:GG:G	acceptor_gain	1.0000

AlphaMissense

2961 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:14649879:T:A	W182R	0.998
16:14649879:T:C	W182R	0.998
16:14655210:G:C	K261N	0.997
16:14655210:G:T	K261N	0.997
16:14649881:G:C	W182C	0.996
16:14649881:G:T	W182C	0.996
16:14655201:G:C	W258C	0.996
16:14655201:G:T	W258C	0.996
16:14655199:T:A	W258R	0.995
16:14655199:T:C	W258R	0.995
16:14649903:T:A	W190R	0.993
16:14649903:T:C	W190R	0.993
16:14649970:G:A	G212E	0.993
16:14649880:G:C	W182S	0.991
16:14649969:G:A	G212R	0.990
16:14649969:G:C	G212R	0.990
16:14649970:G:T	G212V	0.990
16:14644506:T:C	C54R	0.988
16:14644554:T:C	C70R	0.988
16:14649924:T:A	W197R	0.988
16:14649924:T:C	W197R	0.988
16:14649926:G:C	W197C	0.988
16:14649926:G:T	W197C	0.988
16:14667705:T:A	W411R	0.988
16:14667705:T:C	W411R	0.988
16:14644507:G:A	C54Y	0.987
16:14644577:G:C	W77C	0.987
16:14644577:G:T	W77C	0.987
16:14649907:T:C	L191P	0.987
16:14644508:C:G	C54W	0.986

dbSNP variants (sampled 300 via entrez): RS1000083127 (16:14638760 A>G), RS1000183091 (16:14659239 T>A,G), RS1000199007 (16:14636997 A>T), RS1000206553 (16:14668880 C>A,T), RS1000241805 (16:14647765 A>G), RS1000254313 (16:14642450 A>T), RS1000334641 (16:14668939 T>C), RS1000353958 (16:14632584 T>G), RS1000401188 (16:14635940 T>A), RS1000427646 (16:14632432 T>C), RS1000479620 (16:14663032 T>G), RS1000576050 (16:14641223 A>G,T), RS1000580289 (16:14647075 C>T), RS1000632489 (16:14646783 C>A), RS1000634637 (16:14636834 A>G)

Disease associations

OMIM: gene MIM:619516 | disease phenotypes: MIM:616353

GenCC curated gene-disease

Mondo (1): dyskeratosis congenita, autosomal recessive 6 (MONDO:0014600)

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

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Ozone	affects expression, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
VX-agent	increases expression	1
beta-lapachone	increases expression	1
beta-methylcholine	affects expression	1
usnic acid	increases expression	1
abrine	increases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	increases expression	1
Arsenic	affects cotreatment, affects expression	1
Doxorubicin	decreases expression	1
Emodin	decreases expression	1
Folic Acid	affects expression	1
Menthol	decreases expression	1
Paraquat	increases expression	1
Quercetin	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Cadmium Chloride	decreases expression	1
Palmitic Acid	affects cotreatment, affects expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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