BBS9

Summary

BBS9 (Bardet-Biedl syndrome 9, HGNC:30000) is a protein-coding gene on chromosome 7p14.3, encoding Protein PTHB1 (Q3SYG4). The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia.

This gene is downregulated by parathyroid hormone in osteoblastic cells, and therefore is thought to be involved in parathyroid hormone action in bones. The exact function of this gene has not yet been determined. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 27241 — RefSeq curated summary.

At a glance

• Gene–disease (curated): BBS9-related ciliopathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 1,318 total — 81 pathogenic, 71 likely-pathogenic
• Phenotypes (HPO): 110
• MANE Select transcript: NM_198428

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30000
Approved symbol	BBS9
Name	Bardet-Biedl syndrome 9
Location	7p14.3
Locus type	gene with protein product
Status	Approved
Aliases	B1, PTHB1
Ensembl gene	ENSG00000122507
Ensembl biotype	protein_coding
OMIM	607968
Entrez	27241

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 25 protein_coding, 9 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay, 2 retained_intron

ENST00000242067, ENST00000350941, ENST00000355070, ENST00000396127, ENST00000425508, ENST00000432983, ENST00000433714, ENST00000434373, ENST00000442858, ENST00000465037, ENST00000482941, ENST00000489708, ENST00000495426, ENST00000496029, ENST00000498189, ENST00000627264, ENST00000671871, ENST00000671890, ENST00000671952, ENST00000671963, ENST00000672453, ENST00000672717, ENST00000672758, ENST00000672973, ENST00000673056, ENST00000673219, ENST00000673230, ENST00000673431, ENST00000673462, ENST00000893848, ENST00000942907, ENST00000942908, ENST00000942909, ENST00000942910, ENST00000942911, ENST00000942912, ENST00000942913, ENST00000942914, ENST00000942915, ENST00000942916

RefSeq mRNA: 17 — MANE Select: NM_198428 NM_001033604, NM_001033605, NM_001348036, NM_001348037, NM_001348038, NM_001348039, NM_001348040, NM_001348041, NM_001348042, NM_001348043, NM_001348044, NM_001348045, NM_001348046, NM_001362679, NM_001412127, NM_014451, NM_198428

CCDS: CCDS34618, CCDS43566, CCDS47572, CCDS5441, CCDS94079, CCDS94080, CCDS94081, CCDS94082

Canonical transcript exons

ENST00000242067 — 23 exons

Exon	Start	End
ENSE00000976532	33264290	33264374
ENSE00000976533	33273012	33273195
ENSE00000976535	33336441	33336622
ENSE00000976536	33340897	33340973
ENSE00000976537	33344581	33344634
ENSE00001343180	33273827	33273956
ENSE00001343192	33257236	33257410
ENSE00003459271	33367767	33367862
ENSE00003480197	33352859	33352873
ENSE00003485128	33357855	33357995
ENSE00003487291	33177478	33177591
ENSE00003488114	33155638	33155702
ENSE00003494018	33505463	33505645
ENSE00003501426	33349068	33349170
ENSE00003502585	33533954	33534176
ENSE00003503306	33387992	33388144
ENSE00003537498	33383666	33383838
ENSE00003613322	33604865	33604975
ENSE00003622886	33152701	33152851
ENSE00003655860	33351219	33351323
ENSE00003683228	33146242	33146364
ENSE00003895709	33605195	33606069
ENSE00003895719	33129564	33130041

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 95.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.8094 / max 273.2724, expressed in 1519 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
78067	4.3025	1381
78069	1.4564	129
78066	0.7571	481
78065	0.2935	119

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	95.45	gold quality
secondary oocyte	CL:0000655	94.33	gold quality
calcaneal tendon	UBERON:0003701	91.32	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.47	gold quality
endothelial cell	CL:0000115	89.07	gold quality
colonic epithelium	UBERON:0000397	88.72	gold quality
buccal mucosa cell	CL:0002336	88.63	gold quality
cortical plate	UBERON:0005343	87.61	gold quality
adrenal tissue	UBERON:0018303	87.58	gold quality
bronchial epithelial cell	CL:0002328	87.10	gold quality
sural nerve	UBERON:0015488	86.74	gold quality
tendon	UBERON:0000043	86.64	gold quality
right uterine tube	UBERON:0001302	86.51	gold quality
pituitary gland	UBERON:0000007	85.74	gold quality
adenohypophysis	UBERON:0002196	85.63	gold quality
ganglionic eminence	UBERON:0004023	85.63	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.60	gold quality
epithelium of bronchus	UBERON:0002031	84.99	gold quality
bronchus	UBERON:0002185	84.57	gold quality
ventricular zone	UBERON:0003053	84.52	gold quality
sperm	CL:0000019	84.41	gold quality
corpus callosum	UBERON:0002336	84.16	gold quality
thyroid gland	UBERON:0002046	84.08	gold quality
left lobe of thyroid gland	UBERON:0001120	83.93	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.50	gold quality
right lobe of thyroid gland	UBERON:0001119	83.40	gold quality
male germ cell	CL:0000015	83.10	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	82.98	gold quality
choroid plexus epithelium	UBERON:0003911	82.88	gold quality
tibial nerve	UBERON:0001323	82.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.28

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

65 targeting BBS9, 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-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-3128	99.50	67.85	1258
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-143-3P	99.49	69.05	1457

Literature-anchored findings (GeneRIF, showing 15)

• gene is interrupted by a t(1;7)(q42;p15) breakpoint associated with Wilms’ tumour; new alternately spliced isoforms were found in a wide range of adult and foetal tissues (PMID:12618763)
• Comparative genomics and gene expression analysis identifies PHTB1 protein as BBS9, a new Bardet-Biedl syndrome gene. (PMID:16380913)
• PTHB1 is strongly associated with POF, and ht1 confers susceptibility to POF (PMID:18349106)
• Human BBS9 mRNA rescues bbs9 knockdown phenotype in the zebrafish. (PMID:22479622)
• Robust associations with nonsyndromic sagittal craniosynostosis were found in a 120-kb region downstream of BMP2 flanked by rs1884302 and rs6140226 and within a 167-kb region of BBS9 between rs10262453 and rs17724206. (PMID:23160099)
• we report here, for the first time, in Indian population, a novel, different profile of mutations in BBS genes (BBS3, BBS9, BBS10 and BBS2) compared to worldwide (BBS1 and 10) reports. (PMID:24400638)
• The endoplasmic reticulum membrane J protein C18 executes a distinct role in promoting simian virus 40 membrane penetration. (PMID:25631089)
• BBS9 has four folded domains, based on structure prediction; the N-terminal domain is a beta-propeller. (PMID:26085087)
• Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women (PMID:26480920)
• BBS9/PTHB1 gene mutations have been shown to be associated with Bardet Biedl syndrome and to the best of our knowledge this study reports the first Pakistani family linked to the BBS9 gene. (PMID:26846096)
• BBS9 functional knockdown affected the expression of primary cilia on patient suture cells and their osteogenic potential. (PMID:29674126)
• Study of two apparently unrelated consanguineous Bardet-Biedle syndrome families from Dera Ismail Khan (D.I.Khan) district, Pakistan identified a recently reported single base deletion NM_001033604.1:c.299delC in the fourth exon of BBS9 in both families and speculate the evolutionary significance of this mutation and assume its strong founder effect in the Khaisoori tribe of D.I.Khan. (PMID:31294530)
• Authors found that within this structure, BBS2 and BBS7 form a tight dimer through a coiled-coil interaction and that BBS9 associates with the dimer via an interaction with the alpha-helical domain of BBS2. Interestingly, a BBS-associated mutation of BBS2 is located in its alpha-helical domain at the interface between BBS2 and BBS9, and binding experiments indicated that this mutation disrupts the BBS2-BBS9 interaction. (PMID:31530639)
• Next-Generation Sequencing in the Diagnosis of Patients with Bardet-Biedl Syndrome-New Variants and Relationship with Hyperglycemia and Insulin Resistance. (PMID:33138063)
• A Novel BBS9 Mutation Identified via Whole-Exome Sequencing in a Chinese Family with Bardet-Biedl Syndrome. (PMID:34692830)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	bbs9	ENSDARG00000079217
mus_musculus	Bbs9	ENSMUSG00000035919
rattus_norvegicus	Bbs9	ENSRNOG00000015189
drosophila_melanogaster	BBS9	FBGN0034622
caenorhabditis_elegans	bbs-9	WBGENE00016744

Protein

Protein identifiers

Protein PTHB1 — Q3SYG4 (reviewed: Q3SYG4)

Alternative names: Bardet-Biedl syndrome 9 protein, Parathyroid hormone-responsive B1 gene protein

All UniProt accessions (14): A0A090N7W2, A0A090N8P4, A0A5F9ZGX9, A0A5F9ZGY2, A0A5F9ZH06, A0A5F9ZH14, A0A5F9ZH37, A0A5F9ZH74, A0A5F9ZHE7, A0A5F9ZHP5, C9JJ08, Q3SYG4, F8WCG5, H7BZ69

UniProt curated annotations — full annotation on UniProt →

Function. The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia. The BBSome complex is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Firstly the BBSome associates with the ciliary membrane and binds to RAB3IP/Rabin8, the guanosyl exchange factor (GEF) for Rab8 and then the Rab8-GTP localizes to the cilium and promotes docking and fusion of carrier vesicles to the base of the ciliary membrane. Required for proper BBSome complex assembly and its ciliary localization.

Subunit / interactions. Part of BBSome complex, that contains BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10. Interacts with LZTL1; the interaction mediates the association of LZTL1 with the BBsome complex and regulates BBSome ciliary trafficking.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Cell projection. Cilium membrane. Centriolar satellite.

Tissue specificity. Widely expressed. Expressed in adult heart, skeletal muscle, lung, liver, kidney, placenta and brain, and in fetal kidney, lung, liver and brain.

Disease relevance. A chromosomal aberration involving PTHB1 has been found in Wilms tumor. Translocation t(1;7)(q42;p15) with OBSCN. Bardet-Biedl syndrome 9 (BBS9) [MIM:615986] A syndrome characterized by usually severe pigmentary retinopathy, early-onset obesity, polydactyly, hypogenitalism, renal malformation and intellectual disability. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. The disease is caused by variants affecting the gene represented in this entry.

Induction. Down-regulated by parathyroid hormone.

Isoforms (7)

UniProt ID	Names	Canonical?
Q3SYG4-1	1	yes
Q3SYG4-2	2
Q3SYG4-3	3
Q3SYG4-4	4
Q3SYG4-5	5
Q3SYG4-6	6
Q3SYG4-7	7

RefSeq proteins (17): NP_001028776, NP_001028777, NP_001334965, NP_001334966, NP_001334967, NP_001334968, NP_001334969, NP_001334970, NP_001334971, NP_001334972, NP_001334973, NP_001334974, NP_001334975, NP_001349608, NP_001399056, NP_055266, NP_940820* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026511	PTHB1	Family
IPR028073	PHTB1_N_dom	Domain
IPR028074	PHTB1_GAE_dom	Domain
IPR055362	PTHB1_pf_dom	Domain
IPR055363	PTHB1_hp_dom	Domain
IPR055364	PTHB1_CtH_dom	Domain

Pfam: PF14727, PF14728, PF23337, PF23338, PF23339

UniProt features (59 total): strand 28, splice variant 9, sequence variant 8, region of interest 3, turn 3, mutagenesis site 2, sequence conflict 2, helix 2, chain 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4YD8	X-RAY DIFFRACTION	1.8
6XT9	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q3SYG4-F1	85.41	0.63

Functional residue map

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

Catalytic / active sites (1): 141 (critical for protein stability)

Mutagenesis-validated functional residues (2):

Position	Phenotype
142	fails to restore protein stability; when associated with pathogenic variant bbs9 r-141.
186	fails to restore protein stability; when associated with pathogenic variant bbs9 r-141.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5620922	BBSome-mediated cargo-targeting to cilium

MSigDB gene sets: 417 (showing top): GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, SCIBETTA_KDM5B_TARGETS_UP, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_CILIUM_ORGANIZATION, OUELLET_CULTURED_OVARIAN_CANCER_INVASIVE_VS_LMP_DN, GOCC_CENTROSOME, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOBP_ORGANELLE_ASSEMBLY, GOBP_FAT_CELL_DIFFERENTIATION, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_SENSORY_PERCEPTION, GOBP_CELL_PROJECTION_ORGANIZATION

GO Biological Process (6): visual perception (GO:0007601), protein transport (GO:0015031), fat cell differentiation (GO:0045444), cilium assembly (GO:0060271), protein localization to cilium (GO:0061512), cell projection organization (GO:0030030)

GO Molecular Function (2): molecular_function (GO:0003674), protein binding (GO:0005515)

GO Cellular Component (19): pericentriolar material (GO:0000242), acrosomal vesicle (GO:0001669), nucleoplasm (GO:0005654), centriole (GO:0005814), cytosol (GO:0005829), cilium (GO:0005929), membrane (GO:0016020), centriolar satellite (GO:0034451), BBSome (GO:0034464), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), ciliary membrane (GO:0060170), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), cytoplasm (GO:0005737), centrosome (GO:0005813), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cargo trafficking to the periciliary membrane	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	10
cilium	4
microtubule organizing center	3
centrosome	2
intracellular membraneless organelle	2
sperm flagellum	2
sensory perception of light stimulus	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
cell differentiation	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
protein localization to organelle	1
cellular component organization	1
binding	1
secretory granule	1
nuclear lumen	1
cytoplasm	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
protein-containing complex	1
cell projection membrane	1
bounding membrane of organelle	1
intracellular anatomical structure	1
centriole	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

99 interactions, top by confidence:

A	B	Type	Score
IQCB1	CEP290	psi-mi:“MI:0914”(association)	0.950
BBS1	BBS9	psi-mi:“MI:0915”(physical association)	0.940
BBS9	BBS1	psi-mi:“MI:0915”(physical association)	0.940
BBS1	BBS9	psi-mi:“MI:0914”(association)	0.940
BBS9	BBS2	psi-mi:“MI:0915”(physical association)	0.920
BBS2	BBS9	psi-mi:“MI:0915”(physical association)	0.920
BBS2	BBS9	psi-mi:“MI:0914”(association)	0.920
BBS2	BBS9	psi-mi:“MI:0403”(colocalization)	0.920
BBS4	PCM1	psi-mi:“MI:0914”(association)	0.910
BBS5	BBS9	psi-mi:“MI:0914”(association)	0.890
BBS5	BBS9	psi-mi:“MI:0915”(physical association)	0.890
BBS9	BBS5	psi-mi:“MI:0915”(physical association)	0.890

BioGRID (33): BBS9 (Affinity Capture-MS), BBS9 (Affinity Capture-MS), BBS9 (Affinity Capture-MS), BBS9 (Affinity Capture-MS), BBS9 (Affinity Capture-MS), BBS9 (Affinity Capture-MS), BBS9 (Affinity Capture-MS), BBS9 (Affinity Capture-MS), BBS9 (Affinity Capture-MS), BBS9 (Affinity Capture-MS), BBS9 (Affinity Capture-MS), BBS9 (Affinity Capture-MS), BBS9 (Affinity Capture-MS), BBS5 (Affinity Capture-MS), BBS9 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8F8I9, A0A2R8QPS5, A1A5P5, A7S2N8, B0BM28, B4FGS2, B8AXB6, B8B624, B8JKF4, B9FM64, F1QNV4, F4IQJ2, P49842, P97564, Q08CY4, Q08DB2, Q0P5W1, Q0VA04, Q14AI0, Q2KI89, Q32PH0, Q3SYG4, Q3U0M1, Q4R804, Q5R629, Q61586, Q66I84, Q68F70, Q6DHG8, Q6GL75, Q6GMB0, Q6GN08, Q6GPP1, Q6NU25, Q6PA97, Q7T006, Q7XAM0, Q7Z3E5, Q811G0, Q8CIM8

Diamond homologs: Q3SYG4, Q6AX60, Q811G0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
BBS9	“form complex”	“BBsome complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 42 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
BBSome-mediated cargo-targeting to cilium	12	186.2×	6e-24
Cargo trafficking to the periciliary membrane	11	85.3×	1e-17
Cilium Assembly	14	47.6×	6e-19
Organelle biogenesis and maintenance	14	28.9×	4e-16
Anchoring of the basal body to the plasma membrane	5	17.7×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
melanosome transport	5	100.8×	9e-08
non-motile cilium assembly	9	68.8×	9e-13
photoreceptor cell maintenance	6	56.6×	9e-08
fat cell differentiation	7	33.4×	9e-08
cilium assembly	14	27.1×	1e-14
visual perception	7	14.6×	2e-05
protein transport	7	8.1×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1318 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	81
Likely pathogenic	71
Uncertain significance	491
Likely benign	505
Benign	63

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070393	NC_000007.13:g.(?33185855)(33195324_?)del	Pathogenic
1073901	NM_198428.3(BBS9):c.2097dup (p.Asp700fs)	Pathogenic
1074680	NM_198428.3(BBS9):c.2007_2008dup (p.Ala670fs)	Pathogenic
1074830	NM_198428.3(BBS9):c.1789C>T (p.Gln597Ter)	Pathogenic
1344653	NM_198428.3(BBS9):c.542C>G (p.Pro181Arg)	Pathogenic
1400532	NM_198428.3(BBS9):c.263+1G>T	Pathogenic
1405592	NM_198428.3(BBS9):c.2536del (p.Ile846fs)	Pathogenic
1407455	NM_198428.3(BBS9):c.244del (p.Glu82fs)	Pathogenic
1437824	NM_198428.3(BBS9):c.754del (p.Ser252fs)	Pathogenic
1453911	NM_198428.3(BBS9):c.751dup (p.Val251fs)	Pathogenic
1457217	NC_000007.13:g.(?33296828)(33427776_?)del	Pathogenic
1459407	NC_000007.13:g.(?33136085)(33192483_?)del	Pathogenic
1460323	NC_000007.13:g.(?33296828)(33313588_?)del	Pathogenic
1685565	NM_198428.3(BBS9):c.702+1G>A	Pathogenic
1701520	NM_198428.3(BBS9):c.1120C>T (p.Arg374Ter)	Pathogenic
1899278	NM_198428.3(BBS9):c.839dup (p.Met280fs)	Pathogenic
191219	NM_198428.3(BBS9):c.263C>A (p.Ser88Ter)	Pathogenic
2005706	NM_198428.3(BBS9):c.2368G>T (p.Glu790Ter)	Pathogenic
2032223	NM_198428.3(BBS9):c.459C>A (p.Cys153Ter)	Pathogenic
2093163	NM_198428.3(BBS9):c.763C>T (p.Gln255Ter)	Pathogenic
2158610	NM_198428.3(BBS9):c.358C>T (p.Gln120Ter)	Pathogenic
216143	NM_198428.2(BBS9):c.(?_-1)_328+?del	Pathogenic
217437	NM_198428.3(BBS9):c.104_112+4del	Pathogenic
2427650	NC_000007.13:g.(?33388660)(33388802_?)del	Pathogenic
2427651	NC_000007.13:g.(?33054342)(33185996_?)del	Pathogenic
2427652	NC_000007.13:g.(?33376033)(33427776_?)del	Pathogenic
2427653	NC_000007.13:g.(?33388660)(33397627_?)del	Pathogenic
2498309	NM_198428.3(BBS9):c.1195C>T (p.Gln399Ter)	Pathogenic
2498312	NM_198428.3(BBS9):c.621_702+3del	Pathogenic
2658	NM_198428.3(BBS9):c.2045dup (p.Arg683fs)	Pathogenic

SpliceAI

6906 predictions. Top by Δscore:

Variant	Effect	Δscore
7:33152688:A:AG	acceptor_gain	1.0000
7:33152689:A:AG	acceptor_gain	1.0000
7:33152690:A:G	acceptor_gain	1.0000
7:33152691:T:G	acceptor_gain	1.0000
7:33152697:ACAG:A	acceptor_loss	1.0000
7:33152698:C:G	acceptor_gain	1.0000
7:33152699:A:AC	acceptor_loss	1.0000
7:33152699:A:AG	acceptor_gain	1.0000
7:33152700:G:GC	acceptor_gain	1.0000
7:33152700:GA:G	acceptor_gain	1.0000
7:33152700:GAT:G	acceptor_gain	1.0000
7:33152700:GATA:G	acceptor_gain	1.0000
7:33152700:GATAA:G	acceptor_gain	1.0000
7:33152830:TGG:T	donor_gain	1.0000
7:33152831:GGA:G	donor_gain	1.0000
7:33152832:G:GT	donor_gain	1.0000
7:33152832:G:T	donor_gain	1.0000
7:33152835:G:GG	donor_gain	1.0000
7:33152840:A:T	donor_gain	1.0000
7:33152847:GTTTC:G	donor_gain	1.0000
7:33152848:TTTC:T	donor_gain	1.0000
7:33152849:TTC:T	donor_gain	1.0000
7:33152850:TC:T	donor_gain	1.0000
7:33152851:CG:C	donor_loss	1.0000
7:33152852:GTAA:G	donor_gain	1.0000
7:33152856:G:GG	donor_gain	1.0000
7:33155635:CAGAG:C	acceptor_loss	1.0000
7:33155636:A:AG	acceptor_gain	1.0000
7:33155636:AGAGG:A	acceptor_loss	1.0000
7:33155637:G:GT	acceptor_gain	1.0000

AlphaMissense

5805 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:33155661:C:A	A96D	0.999
7:33155688:T:A	V105D	0.998
7:33273904:T:A	W322R	0.998
7:33273904:T:C	W322R	0.998
7:33146262:T:C	F4L	0.997
7:33146264:T:A	F4L	0.997
7:33146264:T:G	F4L	0.997
7:33152718:A:C	S44R	0.997
7:33152720:C:A	S44R	0.997
7:33152720:C:G	S44R	0.997
7:33152734:T:C	L49P	0.996
7:33155682:T:C	L103P	0.996
7:33336467:T:C	L348P	0.996
7:33336587:T:C	L388P	0.996
7:33388068:T:C	L680P	0.996
7:33533957:T:A	W768R	0.996
7:33533957:T:C	W768R	0.996
7:33273094:T:A	V262D	0.995
7:33273906:G:C	W322C	0.995
7:33273906:G:T	W322C	0.995
7:33383669:G:C	R598P	0.995
7:33383675:G:C	R600P	0.995
7:33146263:T:C	F4S	0.994
7:33146280:T:A	W10R	0.994
7:33146280:T:C	W10R	0.994
7:33152716:G:A	G43D	0.994
7:33152845:T:C	F86S	0.994
7:33155660:G:C	A96P	0.994
7:33257250:T:C	C153R	0.994
7:33257275:T:C	L161P	0.994

dbSNP variants (sampled 300 via entrez): RS1000002438 (7:33214875 A>C,G), RS1000008458 (7:33379815 G>A), RS1000008582 (7:33351509 G>T), RS1000011467 (7:33522787 A>G), RS1000018562 (7:33153493 A>G), RS1000021161 (7:33321306 A>G), RS1000025244 (7:33285399 T>C), RS1000025791 (7:33161808 C>T), RS1000041622 (7:33502395 G>A,C), RS1000055852 (7:33220565 A>G), RS1000055862 (7:33603827 C>T), RS1000057810 (7:33285671 A>G,T), RS1000060140 (7:33455687 G>A), RS1000061158 (7:33351066 C>T), RS1000061727 (7:33633385 C>A)

Disease associations

OMIM: gene MIM:607968 | disease phenotypes: MIM:209900, MIM:615986, MIM:181500, MIM:606966, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
Bardet-Biedl syndrome 9	Definitive	Autosomal recessive
Bardet-Biedl syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
BBS9-related ciliopathy	Definitive	AR

Mondo (12): Bardet-Biedl syndrome (MONDO:0015229), Bardet-Biedl syndrome 9 (MONDO:0014437), inherited retinal dystrophy (MONDO:0019118), BBS9-related ciliopathy (MONDO:0700236), schizophrenia (MONDO:0005090), Bardet-Biedl syndrome 1 (MONDO:0008854), primary ovarian failure (MONDO:0005387), nephronophthisis 4 (MONDO:0011752), retinal disorder (MONDO:0005283), neurodevelopmental disorder (MONDO:0700092), retinitis pigmentosa (MONDO:0019200), optic atrophy (MONDO:0003608)

Orphanet (6): Bardet-Biedl syndrome (Orphanet:110), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Nephronophthisis (Orphanet:655), Retinitis pigmentosa (Orphanet:791), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

110 total (30 of 110 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000028	Cryptorchidism
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000085	Horseshoe kidney
HP:0000100	Nephrotic syndrome
HP:0000119	Abnormality of the genitourinary system
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000147	Polycystic ovaries
HP:0000163	Abnormal oral cavity morphology
HP:0000218	High palate
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000388	Otitis media
HP:0000400	Macrotia
HP:0000426	Prominent nasal bridge
HP:0000470	Short neck
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000546	Retinal degeneration
HP:0000548	Cone/cone-rod dystrophy

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST001745_2	Sagittal craniosynostosis	6.000000e-20
GCST002361_24	Smooth-surface caries	4.000000e-06
GCST002982_3	Acute kidney injury in coronary artery bypass surgery (creatinine rise)	2.000000e-07
GCST004009_2	Leprosy	4.000000e-10
GCST005212_25	Asthma	3.000000e-06
GCST005359_14	Disease progression in age-related macular degeneration	1.000000e-06
GCST006412_64	Intraocular pressure	3.000000e-09
GCST007576_206	Chronotype	1.000000e-09
GCST007977_1	Postoperative stroke after cardiac surgery	3.000000e-07
GCST008662_16	Lung function in never smokers (low FEV1 vs high FEV1)	4.000000e-07
GCST009277_1	Subjective response to placebo treatment in childhood asthma (change in cough/wheeze)	1.000000e-07
GCST009725_78	Intraocular pressure	9.000000e-08
GCST010298_1	Metopic nonsyndromic craniosynostosis	3.000000e-08
GCST010702_35	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_323	Brain morphology (MOSTest)	1.000000e-10
GCST010989_117	Body size at age 10	4.000000e-09
GCST90010427_12	Left–right brain asymmetry	4.000000e-08

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0700076	isolated scaphocephaly
EFO:0008336	disease progression measurement
EFO:0004695	intraocular pressure measurement
EFO:0008328	chronotype measurement
EFO:0009951	response to surgery
EFO:0009956	post-operative stroke
EFO:0004314	forced expiratory volume
EFO:0008344	response to placebo
EFO:0010068	respiratory symptom change measurement
EFO:0008511	metopic craniosynostosis
EFO:0004346	neuroimaging measurement
EFO:0009819	comparative body size at age 10, self-reported

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D020788	Bardet-Biedl Syndrome	C10.228.140.617.200; C11.270.684.624; C16.131.077.245.125; C16.320.184.125
D065886	Neurodevelopmental Disorders	F03.625
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C565918	Bardet-Biedl Syndrome 9 (supp.)
C537909	Bardet-Biedl syndrome 1 (supp.)
C564640	Nephronophthisis 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	9
Benzo(a)pyrene	decreases expression, increases expression	5
Aflatoxin B1	affects expression, decreases expression, increases methylation	4
bisphenol A	affects methylation, decreases methylation, increases expression, affects cotreatment	3
Cisplatin	affects expression, affects cotreatment, decreases expression	3
methylmercuric chloride	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Cyclosporine	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
trichostatin A	affects expression	1
cobaltous chloride	affects expression	1
potassium chromate(VI)	decreases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	increases expression	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects methylation, affects cotreatment	1
Arsenic	affects methylation	1
Vehicle Emissions	increases abundance, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety