BEST3

Summary

BEST3 (bestrophin 3, HGNC:17105) is a protein-coding gene on chromosome 12q15, encoding Bestrophin-3 (Q8N1M1). Ligand-gated anion channel that allows the movement of chloride monoatomic anions across cell membranes when activated by calcium (Ca2+).

BEST3 belongs to the bestrophin family of anion channels, which includes BEST1 (MIM 607854), the gene mutant in vitelliform macular dystrophy (VMD; MIM 153700), and 2 other BEST1-like genes, BEST2 (MIM 607335) and BEST4 (MIM 607336). Bestrophins are transmembrane (TM) proteins that share a homology region containing a high content of aromatic residues, including an invariant arg-phe-pro (RFP) motif. The bestrophin genes share a conserved gene structure, with almost identical sizes of the 8 RFP-TM domain-encoding exons and highly conserved exon-intron boundaries. Each of the 4 bestrophin genes has a unique 3-prime end of variable length (Stohr et al., 2002 [PubMed 12032738]; Tsunenari et al., 2003 [PubMed 12907679]).

Source: NCBI Gene 144453 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 103 total — 3 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_032735

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17105
Approved symbol	BEST3
Name	bestrophin 3
Location	12q15
Locus type	gene with protein product
Status	Approved
Aliases	MGC40411, MGC13168
Ensembl gene	ENSG00000127325
Ensembl biotype	protein_coding
OMIM	607337
Entrez	144453

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000266661, ENST00000330891, ENST00000331471, ENST00000476098, ENST00000488961, ENST00000529843, ENST00000533674, ENST00000547208, ENST00000548658, ENST00000551160, ENST00000552295, ENST00000553096, ENST00000944745

RefSeq mRNA: 6 — MANE Select: NM_032735 NM_001282613, NM_001282614, NM_001282615, NM_001282616, NM_032735, NM_152439

CCDS: CCDS41810, CCDS61192, CCDS61193, CCDS73496, CCDS8992

Canonical transcript exons

ENST00000330891 — 10 exons

Exon	Start	End
ENSE00001294773	69671428	69671579
ENSE00001319593	69676916	69677068
ENSE00001423775	69699205	69699303
ENSE00001910204	69653609	69655813
ENSE00003251214	69677180	69677257
ENSE00003318513	69672885	69672965
ENSE00003494773	69678739	69678893
ENSE00003500049	69694370	69694464
ENSE00003569612	69693674	69693907
ENSE00003572303	69697647	69697813

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 96.96.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.7485 / max 431.2756, expressed in 168 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
132028	0.6810	92
132030	0.6561	120
132029	0.2573	53
132031	0.0711	28
132032	0.0465	22
132033	0.0365	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibialis anterior	UBERON:0001385	96.96	gold quality
gastrocnemius	UBERON:0001388	95.40	gold quality
muscle of leg	UBERON:0001383	93.66	gold quality
deltoid	UBERON:0001476	91.48	gold quality
sperm	CL:0000019	91.05	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.38	gold quality
skeletal muscle tissue	UBERON:0001134	88.08	gold quality
quadriceps femoris	UBERON:0001377	88.04	gold quality
vastus lateralis	UBERON:0001379	86.99	gold quality
biceps brachii	UBERON:0001507	85.87	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	84.61	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	82.68	gold quality
muscle tissue	UBERON:0002385	81.49	gold quality
cerebellar hemisphere	UBERON:0002245	77.01	gold quality
pancreatic ductal cell	CL:0002079	76.95	gold quality
cerebellar cortex	UBERON:0002129	76.92	gold quality
right hemisphere of cerebellum	UBERON:0014890	76.39	gold quality
islet of Langerhans	UBERON:0000006	75.69	gold quality
cerebellum	UBERON:0002037	75.47	gold quality
bone marrow cell	CL:0002092	73.54	gold quality
body of tongue	UBERON:0011876	72.78	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.32	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	69.28	gold quality
amygdala	UBERON:0001876	68.83	gold quality
adrenal tissue	UBERON:0018303	67.91	gold quality
bone marrow	UBERON:0002371	66.89	gold quality
cerebellar vermis	UBERON:0004720	66.79	gold quality
spinal cord	UBERON:0002240	66.69	gold quality
anterior cingulate cortex	UBERON:0009835	65.73	gold quality
tongue	UBERON:0001723	65.17	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.97
E-GEOD-93593	yes	4.05
E-MTAB-9801	no	2.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

90 targeting BEST3, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-499A-5P	99.98	70.79	1323
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-8075	99.97	67.20	962
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
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-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509

Literature-anchored findings (GeneRIF, showing 5)

• identified three novel VMD2-related human genes demonstrating a high degree of conservation in their respective RFP-TM domains [VMD2L1, VMD2L2, VMD2L3] (PMID:12032738)
• These results suggest that an auto-inhibitory mechanism in C termini of bestrophin 3 may be universal among bestrophins investigated in the study. (PMID:17442670)
• Results provide evidence that the bestrophins are expressed in pancreatic duct cells and, more specifically, that hBest1 plays a role in the calcium activated chloride channels found in these cells. (PMID:19237432)
• results demonstrated that Best-3 is an endogenous inhibitor of NF-kappaB signaling pathway in endothelial cells, suggesting that forced Best-3 expression may be a novel approach for the treatment of vascular inflammatory diseases. (PMID:25329324)
• whole-exome sequencing implicates a rare non-synonymous single-nucleotide variants of BEST3 as a candidate for mandibular prognathism in the Japanese pedigree. (PMID:30849546)

Cross-species orthologs

22 orthologs

Organism	Symbol	Gene ID
mus_musculus	Best3	ENSMUSG00000020169
rattus_norvegicus	Best3	ENSRNOG00000005491
drosophila_melanogaster	Best4	FBGN0036491
drosophila_melanogaster	Best3	FBGN0036492
drosophila_melanogaster	Best1	FBGN0040238
caenorhabditis_elegans		WBGENE00007203
caenorhabditis_elegans		WBGENE00007204
caenorhabditis_elegans		WBGENE00007404
caenorhabditis_elegans		WBGENE00007808
caenorhabditis_elegans	best-8	WBGENE00007988
caenorhabditis_elegans	best-10	WBGENE00008185
caenorhabditis_elegans	best-11	WBGENE00008186
caenorhabditis_elegans		WBGENE00008821
caenorhabditis_elegans		WBGENE00013520
caenorhabditis_elegans	best-25	WBGENE00014102
caenorhabditis_elegans	best-26	WBGENE00014103
caenorhabditis_elegans		WBGENE00015628
caenorhabditis_elegans		WBGENE00020046
caenorhabditis_elegans		WBGENE00021368
caenorhabditis_elegans		WBGENE00022797
caenorhabditis_elegans		WBGENE00206487
caenorhabditis_elegans		WBGENE00220250

Paralogs (3): BEST2 (ENSG00000039987), BEST4 (ENSG00000142959), BEST1 (ENSG00000167995)

Protein

Protein identifiers

Bestrophin-3 — Q8N1M1 (reviewed: Q8N1M1)

Alternative names: Vitelliform macular dystrophy 2-like protein 3

All UniProt accessions (5): Q8N1M1, E9PNM2, F8VR37, F8VVX2, F8VZR0

UniProt curated annotations — full annotation on UniProt →

Function. Ligand-gated anion channel that allows the movement of chloride monoatomic anions across cell membranes when activated by calcium (Ca2+).

Subcellular location. Cell membrane.

Tissue specificity. Present in skeletal muscle and weakly in brain, spinal cord, bone marrow and retina.

Similarity. Belongs to the anion channel-forming bestrophin (TC 1.A.46) family. Calcium-sensitive chloride channel subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8N1M1-2	2	yes
Q8N1M1-1	1
Q8N1M1-4	4
Q8N1M1-5	5
Q8N1M1-6	6

RefSeq proteins (6): NP_001269542, NP_001269543, NP_001269544, NP_001269545, NP_116124, NP_689652 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000615	Bestrophin	Family
IPR021134	Bestrophin-like	Family

Pfam: PF01062

Catalyzed reactions (Rhea), 1 shown:

• chloride(in) = chloride(out) (RHEA:29823)

UniProt features (30 total): splice variant 7, topological domain 5, binding site 5, transmembrane region 4, region of interest 3, compositionally biased region 3, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N1M1-F1	67.66	0.50

Functional residue map

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

Ligand- & substrate-binding residues (5): 10 (in other chain); 293; 296; 301; 304

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-382551	Transport of small molecules
R-HSA-983712	Ion channel transport

MSigDB gene sets: 115 (showing top): MYOGENIN_Q6, GCANCTGNY_MYOD_Q6, GOBP_INORGANIC_ANION_TRANSPORT, TGACCTY_ERR1_Q2, CAGCTG_AP4_Q5, TCF4_Q5, CAGCAGG_MIR370, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_CHLORIDE_TRANSPORT, TGCTGAY_UNKNOWN, WTGAAAT_UNKNOWN, TCF11_01, NIKOLSKY_BREAST_CANCER_12Q13_Q21_AMPLICON, MYOD_Q6, NKX25_01

GO Biological Process (6): negative regulation of monoatomic ion transport (GO:0043271), chloride transmembrane transport (GO:1902476), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), inorganic anion transport (GO:0015698), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (6): intracellularly calcium-gated chloride channel activity (GO:0005229), chloride channel activity (GO:0005254), metal ion binding (GO:0046872), ligand-gated monoatomic anion channel activity (GO:0099095), protein binding (GO:0005515), channel activity (GO:0015267)

GO Cellular Component (3): plasma membrane (GO:0005886), chloride channel complex (GO:0034707), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic ion transport	2
transport	2
monoatomic anion channel activity	2
regulation of monoatomic ion transport	1
negative regulation of transport	1
chloride transport	1
monoatomic anion transmembrane transport	1
monoatomic anion transport	1
inorganic anion transport	1
transmembrane transport	1
chloride channel activity	1
ligand-gated monoatomic anion channel activity	1
intracellularly calcium-gated channel activity	1
chloride transmembrane transporter activity	1
cation binding	1
ligand-gated monoatomic ion channel activity	1
binding	1
passive transmembrane transporter activity	1
membrane	1
cell periphery	1
monoatomic ion channel complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

482 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BEST3	DDIT3	P0DPQ6	578
BEST3	LRRC10	Q5BKY1	550
BEST3	CCT2	P78371	539
BEST3	FRS2	Q8WU20	493
BEST3	ANO1	Q5XXA6	480
BEST3	TFF3	Q07654	475
BEST3	LRRC8A	Q8IWT6	458
BEST3	CLCN3	P51790	453
BEST3	LRRC8B	Q6P9F7	450
BEST3	UNC80	Q8N2C7	449
BEST3	TSPAN31	Q12999	444
BEST3	CLCA2	Q9UQC9	443
BEST3	ATP23	Q9Y6H3	433
BEST3	CNGA2	Q16280	427
BEST3	CLCA4	Q14CN2	420

IntAct

2 interactions, top by confidence:

A	B	Type	Score
P		psi-mi:“MI:0914”(association)	0.350

BioGRID (1): BEST3 (Two-hybrid)

ESM2 similar proteins: A0A0U1QT59, A2VEY9, A8X9H4, D3KZG3, O35412, O35607, O57474, O61366, O93383, P18861, P29415, P34535, P36383, P43322, P49414, P50605, P60571, P91682, Q02297, Q03345, Q05199, Q11069, Q13873, Q14693, Q2THW7, Q2THW9, Q2THX1, Q5R838, Q5RJX2, Q5YCC7, Q64448, Q69ZW3, Q6DR98, Q6H1V1, Q6IMP4, Q6TYA8, Q7TQ69, Q7Z5M5, Q86B91, Q8INR6

Diamond homologs: E1BF86, O18304, O45435, O76090, O88870, P34319, P34577, P34672, Q17528, Q17529, Q17851, Q19978, Q21973, Q22566, Q23369, Q6H1V1, Q6UY87, Q8BGM5, Q8N1M1, Q8NFU0, Q8NFU1, Q8WMR7, Q94175, O18303, O45363

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	85
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
154378	GRCh38/hg38 12q14.3-15(chr12:65445176-71026337)x1	Pathogenic
4682805	GRCh37/hg19 12q15-21.1(chr12:68168330-72795051)x1	Pathogenic
980441	GRCh37/hg19 12q15(chr12:68572386-70833868)x1	Pathogenic
3063262	GRCh37/hg19 12q15-21.1(chr12:69498859-74073631)x1	Likely pathogenic

SpliceAI

1918 predictions. Top by Δscore:

Variant	Effect	Δscore
12:69671423:CTTA:C	donor_loss	1.0000
12:69671424:TTA:T	donor_loss	1.0000
12:69671425:TAC:T	donor_loss	1.0000
12:69671426:A:AC	donor_gain	1.0000
12:69671426:AC:A	donor_gain	1.0000
12:69671426:ACC:A	donor_gain	1.0000
12:69671426:ACCC:A	donor_gain	1.0000
12:69671427:C:A	donor_loss	1.0000
12:69671427:C:CC	donor_gain	1.0000
12:69671427:CC:C	donor_gain	1.0000
12:69671427:CCC:C	donor_gain	1.0000
12:69671427:CCCC:C	donor_gain	1.0000
12:69671427:CCCCA:C	donor_gain	1.0000
12:69676925:T:TA	donor_gain	1.0000
12:69676982:ATGC:A	donor_gain	1.0000
12:69676993:AG:A	donor_gain	1.0000
12:69678737:A:AC	donor_gain	1.0000
12:69678738:C:CC	donor_gain	1.0000
12:69678738:CAGT:C	donor_gain	1.0000
12:69699200:CTAA:C	donor_loss	1.0000
12:69699201:TAA:T	donor_loss	1.0000
12:69699202:AAC:A	donor_loss	1.0000
12:69671422:ACTT:A	donor_loss	0.9900
12:69671564:CAG:C	acceptor_gain	0.9900
12:69672879:TCTAA:T	donor_loss	0.9900
12:69672880:CTAA:C	donor_loss	0.9900
12:69672881:TAAC:T	donor_loss	0.9900
12:69672882:AAC:A	donor_loss	0.9900
12:69672883:ACCT:A	donor_loss	0.9900
12:69672884:CCTGC:C	donor_loss	0.9900

AlphaMissense

4396 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:69672894:T:A	R313S	1.000
12:69672894:T:G	R313S	1.000
12:69672937:C:T	G299E	1.000
12:69672952:A:G	L294P	1.000
12:69672952:A:T	L294H	1.000
12:69676920:A:G	L288P	1.000
12:69676924:A:G	W287R	1.000
12:69676924:A:T	W287R	1.000
12:69676926:C:T	G286E	1.000
12:69678816:A:G	W187R	1.000
12:69678816:A:T	W187R	1.000
12:69693723:G:C	S144R	1.000
12:69693723:G:T	S144R	1.000
12:69693725:T:G	S144R	1.000
12:69693754:A:G	L134P	1.000
12:69693781:C:G	R125T	1.000
12:69693878:A:G	W93R	1.000
12:69693878:A:T	W93R	1.000
12:69693898:A:T	V86D	1.000
12:69693903:A:C	F84L	1.000
12:69693903:A:T	F84L	1.000
12:69693905:A:G	F84L	1.000
12:69693907:C:T	G83E	1.000
12:69694377:A:C	F80L	1.000
12:69694377:A:T	F80L	1.000
12:69694379:A:G	F80L	1.000
12:69697729:A:G	W24R	1.000
12:69697729:A:T	W24R	1.000
12:69671566:G:T	A321D	0.999
12:69671567:C:G	A321P	0.999

dbSNP variants (sampled 300 via entrez): RS1000048747 (12:69691777 C>A,T), RS1000130620 (12:69663448 A>G), RS1000155971 (12:69699818 A>T), RS1000160421 (12:69666610 T>C), RS1000219217 (12:69673421 G>A), RS1000297223 (12:69659846 A>G), RS1000404952 (12:69679439 T>C), RS1000453909 (12:69653809 A>C,G), RS1000510682 (12:69654734 G>A,T), RS1000561642 (12:69678924 A>G,T), RS1000633773 (12:69679206 T>C), RS1000795808 (12:69660199 T>C), RS1000885931 (12:69661493 A>C), RS1000917147 (12:69661804 G>A), RS1000997793 (12:69649112 A>G)

Disease associations

OMIM: gene MIM:607337 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004766_14	Triglyceride change in response to fenofibrate in statin-treated type 2 diabetes	9.000000e-07
GCST006061_13	Atrial fibrillation	9.000000e-13
GCST006061_14	Atrial fibrillation	8.000000e-13
GCST007006_11	Logical memory (delayed recall) in normal cognition	4.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007681	triglyceride change measurement
EFO:0004874	memory performance

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs61747221	BEST3		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	3
perfluorooctanoic acid	decreases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Atrazine	increases expression	1
Cisplatin	decreases expression, affects cotreatment	1
Silicon Dioxide	increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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