BEST4

Summary

BEST4 (bestrophin 4, HGNC:17106) is a protein-coding gene on chromosome 1p34.1, encoding Bestrophin-4 (Q8NFU0). Ligand-gated anion channel that allows the movement of anions across cell membranes when activated by Calcium (Ca2+).

This gene is a member of the bestrophin gene family of anion channels. Bestrophin genes share a similar gene structure with highly conserved exon-intron boundaries, but with distinct 3’ ends. Bestrophins are transmembrane proteins that contain a homologous region rich in aromatic residues, including an invariant arg-phe-pro motif. Mutation in one of the family members (bestrophin 1) is associated with vitelliform macular dystrophy. The bestrophin 4 gene is predominantly expressed in the colon.

Source: NCBI Gene 266675 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 51 total
• MANE Select transcript: NM_153274

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17106
Approved symbol	BEST4
Name	bestrophin 4
Location	1p34.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000142959
Ensembl biotype	protein_coding
OMIM	607336
Entrez	266675

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000372207, ENST00000718432, ENST00000881839, ENST00000881840, ENST00000881841, ENST00000881842

RefSeq mRNA: 1 — MANE Select: NM_153274 NM_153274

CCDS: CCDS514

Canonical transcript exons

ENST00000372207 — 9 exons

Exon	Start	End
ENSE00000957410	44787372	44787466
ENSE00000957411	44786463	44786696
ENSE00000957412	44786074	44786228
ENSE00000957413	44785599	44785676
ENSE00000957414	44785108	44785305
ENSE00001141859	44784629	44784783
ENSE00001457190	44783585	44784483
ENSE00001457191	44787554	44788170
ENSE00004035074	44784905	44784985

Expression profiles

Bgee: expression breadth ubiquitous, 157 present calls, max score 96.29.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0493 / max 30.2191, expressed in 7 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12093	0.0493	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	96.29	gold quality
right uterine tube	UBERON:0001302	93.68	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.08	gold quality
transverse colon	UBERON:0001157	83.29	gold quality
rectum	UBERON:0001052	82.18	gold quality
bronchial epithelial cell	CL:0002328	80.35	gold quality
bronchus	UBERON:0002185	79.70	gold quality
colonic mucosa	UBERON:0000317	75.09	gold quality
mucosa of sigmoid colon	UBERON:0004993	72.38	gold quality
small intestine Peyer’s patch	UBERON:0003454	71.51	gold quality
colon	UBERON:0001155	70.77	gold quality
large intestine	UBERON:0000059	70.76	gold quality
intestine	UBERON:0000160	70.17	gold quality
small intestine	UBERON:0002108	69.83	gold quality
duodenum	UBERON:0002114	69.56	gold quality
right adrenal gland cortex	UBERON:0035827	69.55	gold quality
nasal cavity mucosa	UBERON:0001826	68.90	gold quality
oviduct epithelium	UBERON:0004804	68.58	gold quality
right adrenal gland	UBERON:0001233	67.40	gold quality
left adrenal gland cortex	UBERON:0035825	67.27	gold quality
hypothalamus	UBERON:0001898	66.54	gold quality
fallopian tube	UBERON:0003889	66.17	gold quality
left adrenal gland	UBERON:0001234	65.87	gold quality
jejunal mucosa	UBERON:0000399	65.86	gold quality
adrenal cortex	UBERON:0001235	65.83	gold quality
tendon of biceps brachii	UBERON:0008188	65.81	silver quality
right hemisphere of cerebellum	UBERON:0014890	65.09	gold quality
nucleus accumbens	UBERON:0001882	64.79	gold quality
adenohypophysis	UBERON:0002196	64.77	gold quality
cerebellar hemisphere	UBERON:0002245	64.71	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	2274.69
E-MTAB-8410	yes	1758.85
E-CURD-46	yes	1335.67
E-ANND-3	yes	9.29

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting BEST4, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-302D-5P	99.50	69.34	1863
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-589-5P	98.72	66.96	927
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-6765-3P	97.83	64.59	1165
HSA-MIR-409-5P	97.31	68.07	364
HSA-MIR-3690	96.44	65.18	737
HSA-MIR-4471	95.11	66.84	755
HSA-MIR-8059	95.11	66.30	646
HSA-MIR-6753-5P	94.70	64.08	470

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 (PMID:12032738)
• Human Best4 chloride channels on excised membrane patches can be activated by free calcium (Ca2+) on the cytoplasmic side. (PMID:16702355)
• 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)
• BEST2 and BEST4 could be added to the lineage-specific genes of humans intestinal epithelial cells (PMID:24223998)
• Oncogenic potential of BEST4 in colorectal cancer via activation of PI3K/Akt signaling. (PMID:35058597)

Cross-species orthologs

22 orthologs

Organism	Symbol	Gene ID
danio_rerio	best4	ENSDARG00000078455
rattus_norvegicus	Best4	ENSRNOG00000018749
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), BEST3 (ENSG00000127325), BEST1 (ENSG00000167995)

Protein

Protein identifiers

Bestrophin-4 — Q8NFU0 (reviewed: Q8NFU0)

Alternative names: Vitelliform macular dystrophy 2-like protein 2

All UniProt accessions (1): Q8NFU0

UniProt curated annotations — full annotation on UniProt →

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

Subcellular location. Cell membrane.

Tissue specificity. Predominantly found in colon and the weakly in fetal brain, spinal cord, retina, lung, trachea, testis and placenta.

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

RefSeq proteins (1): NP_695006* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000615	Bestrophin	Family
IPR021134	Bestrophin-like	Family

Pfam: PF01062

Catalyzed reactions (Rhea), 2 shown:

• hydrogencarbonate(in) = hydrogencarbonate(out) (RHEA:28695)
• chloride(in) = chloride(out) (RHEA:29823)

UniProt features (24 total): topological domain 5, binding site 5, transmembrane region 4, sequence variant 4, compositionally biased region 3, region of interest 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NFU0-F1	83.51	0.72

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); 308; 311; 316; 319

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: 49 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_CHLORIDE_TRANSPORT, chr1p34, GOBP_ORGANIC_ANION_TRANSPORT, GOBP_BICARBONATE_TRANSPORT, SABATES_COLORECTAL_ADENOMA_DN, GOBP_TRANSMEMBRANE_TRANSPORT, GOCC_CHLORIDE_CHANNEL_COMPLEX, GOCC_TRANSPORTER_COMPLEX, GOCC_MEMBRANE_PROTEIN_COMPLEX, RNCTGNYNRNCTGNY_UNKNOWN, GOMF_GATED_CHANNEL_ACTIVITY, GOMF_PASSIVE_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOMF_MONOATOMIC_ANION_CHANNEL_ACTIVITY

GO Biological Process (5): chloride transmembrane transport (GO:1902476), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), bicarbonate transport (GO:0015701), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (5): intracellularly calcium-gated chloride channel activity (GO:0005229), chloride channel activity (GO:0005254), metal ion binding (GO:0046872), bicarbonate channel activity (GO:0160133), 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
transport	2
chloride transport	1
monoatomic anion transmembrane transport	1
monoatomic anion transport	1
inorganic anion transport	1
monoatomic ion transport	1
transmembrane transport	1
chloride channel activity	1
ligand-gated monoatomic anion channel activity	1
intracellularly calcium-gated channel activity	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
cation binding	1
bicarbonate transmembrane transporter activity	1
channel activity	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

386 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BEST4	OTOP2	Q7RTS6	741
BEST4	TMEM82	A0PJX8	451
BEST4	C11orf86	A6NJI1	449
BEST4	CA7	P43166	447
BEST4	GUCA2B	Q16661	447
BEST4	CNGA2	Q16280	427
BEST4	TMIGD1	Q6UXZ0	417
BEST4	ANO1	Q5XXA6	393
BEST4	MS4A12	Q9NXJ0	379
BEST4	GUCA2A	Q02747	359
BEST4	LRRC8A	Q8IWT6	356
BEST4	IQCF6	A8MYZ5	348
BEST4	RPE65	Q16518	347
BEST4	DEPDC1	Q5TB30	347
BEST4	CLCA1	A8K7I4	346

IntAct

2 interactions, top by confidence:

A	B	Type	Score
Dlg4	BEST4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (1): BEST4 (Positive Genetic)

ESM2 similar proteins: A0A2K3DU55, A2X8W3, A2XFU4, A2XFU5, A2YQ58, A6YCJ2, A8IF44, A8J1V4, A8JAF2, E9PXX9, O00337, O24594, O62667, P15575, P18080, P33897, P41975, P48768, P48777, Q07307, Q0C8L9, Q0D3F2, Q0DSH9, Q10MI9, Q13488, Q2KIF8, Q39586, Q3E7D0, Q5GA22, Q5JMH0, Q5NAI7, Q5RKL7, Q5Z678, Q5ZHX9, Q62674, Q6Z0Q9, Q750Y9, Q75AT3, Q7XKI5, Q852F6

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, O45363, O18303

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1320 predictions. Top by Δscore:

Variant	Effect	Δscore
1:44784982:CCAC:C	acceptor_gain	1.0000
1:44784983:CAC:C	acceptor_gain	1.0000
1:44784983:CACC:C	acceptor_gain	1.0000
1:44784984:ACCTA:A	acceptor_loss	1.0000
1:44784985:CCT:C	acceptor_loss	1.0000
1:44784985:CCTA:C	acceptor_gain	1.0000
1:44784986:C:CC	acceptor_gain	1.0000
1:44784987:T:G	acceptor_loss	1.0000
1:44785103:CCCA:C	donor_loss	1.0000
1:44785104:CCA:C	donor_loss	1.0000
1:44785105:CAC:C	donor_loss	1.0000
1:44785106:A:AT	donor_loss	1.0000
1:44785107:CCTT:C	donor_loss	1.0000
1:44785260:C:CT	acceptor_gain	1.0000
1:44785264:C:CT	acceptor_gain	1.0000
1:44785264:C:T	acceptor_gain	1.0000
1:44785265:A:T	acceptor_gain	1.0000
1:44785275:C:CT	acceptor_gain	1.0000
1:44785302:CCAC:C	acceptor_gain	1.0000
1:44785303:CACC:C	acceptor_gain	1.0000
1:44785306:CTGG:C	acceptor_loss	1.0000
1:44785307:T:A	acceptor_loss	1.0000
1:44785597:A:AC	donor_gain	1.0000
1:44785598:C:CC	donor_gain	1.0000
1:44786070:TCACT:T	donor_loss	1.0000
1:44786071:CACT:C	donor_loss	1.0000
1:44786072:A:AC	donor_gain	1.0000
1:44786072:ACT:A	donor_loss	1.0000
1:44786072:ACTT:A	donor_gain	1.0000
1:44786073:C:CA	donor_gain	1.0000

AlphaMissense

3048 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:44784915:C:G	R328P	1.000
1:44784916:G:T	R328S	0.999
1:44784938:A:C	F320L	0.999
1:44784938:A:T	F320L	0.999
1:44784939:A:G	F320S	0.999
1:44784940:A:G	F320L	0.999
1:44784942:T:A	D319V	0.999
1:44784957:C:A	G314V	0.999
1:44784957:C:T	G314D	0.999
1:44784963:G:T	P312Q	0.999
1:44784965:G:C	N311K	0.999
1:44784965:G:T	N311K	0.999
1:44785116:A:G	W302R	0.999
1:44785116:A:T	W302R	0.999
1:44785660:C:G	R218P	0.999
1:44786151:A:G	W187R	0.999
1:44786151:A:T	W187R	0.999
1:44786166:A:G	W182R	0.999
1:44786166:A:T	W182R	0.999
1:44786491:G:C	F151L	0.999
1:44786491:G:T	F151L	0.999
1:44786492:A:G	F151S	0.999
1:44786493:A:G	F151L	0.999
1:44786512:G:C	S144R	0.999
1:44786512:G:T	S144R	0.999
1:44786513:C:A	S144I	0.999
1:44786514:T:G	S144R	0.999
1:44786543:A:G	L134P	0.999
1:44786567:C:G	R126P	0.999
1:44786571:G:T	R125S	0.999

dbSNP variants (sampled 300 via entrez): RS1000240950 (1:44783661 C>A,G), RS1000354138 (1:44791731 T>C), RS1000575768 (1:44789312 A>C), RS1000806339 (1:44792927 T>C), RS1000808627 (1:44792032 C>T), RS1001055194 (1:44794554 C>T), RS1001092917 (1:44793185 T>C), RS1001148275 (1:44794170 C>T), RS1001239815 (1:44792461 C>T), RS1001686246 (1:44784365 G>C,T), RS1002135708 (1:44784527 C>A), RS1002345260 (1:44788306 C>T), RS1002398853 (1:44781480 T>C), RS1002510939 (1:44784812 T>A), RS1002914878 (1:44793879 A>C)

Disease associations

OMIM: gene MIM:607336 | 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

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, affects cotreatment	7
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
afuresertib	increases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	decreases methylation	1
trichostatin A	decreases expression	1
sodium arsenite	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation	1
N-Nitrosopyrrolidine	decreases expression	1
Oxygen	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Cyclosporine	decreases expression	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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