BBS7
protein-codingBardet-Biedl syndrome 7, the group of BBSome
Gene summary
This gene encodes one of eight proteins that form the BBSome complex containing BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBIP10. The BBSome complex is believed to recruit Rab8(GTP) to the primary cilium and promote ciliogenesis. The BBSome complex assembly is mediated by a complex composed of three chaperonin-like BBS proteins (BBS6, BBS10, and BBS12) and CCT/TRiC family chaperonins. Mutations in this gene are implicated in Bardet-Biedl syndrome, a genetic disorder whose symptoms include obesity, retinal degeneration, polydactyly and nephropathy; however, mutations in this gene and the BBS8 gene are thought to play a minor role and mutations in chaperonin-like BBS genes are found to be a major contributor to disease development in a multiethnic Bardet-Biedl syndrome patient population. Two transcript variants encoding distinct isoforms have been identified for this gene.[provided by RefSeq, Oct 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~46.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014435
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:1040042
Submitter: ClinGen
The *BBS7* gene was first reported in relation to Bardet-Biedl syndrome in a 2003 report of an affected individual from a consanguineous family (PMID: 12567324). Subsequent publications have established that cases diagnosed with Bardet-Biedl syndrome 7 exhibit retinal disease as the most penetrant feature, characterized by retinal dystrophy, often in a cone-rod pattern, photoreceptor layer loss, pigmentary retinopathy, reduced visual acuity, and/or retinal arteriolar constriction. These phenotypes are generally accompanied by diverse extraocular features such as obesity, polydactyly, renal abnormalities including cysts, abnormal morphology of the heart and/or liver, dental abnormalities such as crowding, hypoplastic external genitalia in males, and/or intellectual disability. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic *BBS7* loss of function) were found to be consistent among patients diagnosed with Bardet-Biedl syndrome 7 (MIM# 615984), while the phenotypic variability between cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic *BBS7* variants have been lumped into a single disease entity, referred to as BBS7-related ciliopathy. Nine suspected disease-causing variants have been scored as part of this curation (two nonsense, five frameshift, one affecting splicing, and one missense), which have been collectively reported in seven probands in seven publications (PMID: 12567324, PMID: 19402160, PMID: 24849935, PMID: 25553308, PMID: 26557828, PMID: 26518167, PMID: 30839500). All of the probands scored in this curation harbored biallelic *BBS7* variants. The mechanism of pathogenicity appears to be biallelic loss of BBS7 function conferred by null and/or hypomorphic variants. Only two relatively small families were found in the literature (PMID: 12567324, PMID: 30839500), and segregation evidence did not contribute to the scoring of this curation. This gene-disease association is also supported by biochemical evidence that *BBS7* encodes a component of the BBSome, a protein complex that functions in ciliogenesis and intraflagellar transport (PMID: 17574030). Consistent with these functions, BBS7 protein localizes to transition zones and ciliary axonemes and dynamically moves in both anterograde and retrograde directions along the ciliary axoneme (PMID: 15231740). BBS7 co-immunoprecipitates with BBS4 (PMID: 17574030), and the genes encoding other BBSome components have similarly been asserted in connection with various monogenic forms of Bardet-Biedl syndrome, including *BBS1* (PMID: 12118255), *BBS2* (PMID: 11285252), *ARL6* (PMID: 15258860), *BBS4* (PMID: 11381270), *BBS5* (PMID: 15137946), *MKKS* (PMID: 10973238, PMID: 10973251), and *TTC8* (PMID: 14520415). *C. elegans* with biallelic *Bbs-7* disruption exhibit short cilia and defects in cilia-based chemotaxis and intraflagellar transport (PMID: 15231740), while *bbs7* knockdown in zebrafish disrupts the ciliated organ controlling left-right patterning and triggers a defect in intracellular retrograde transport of melanosomes (PMID: 16399798). Biallelic disruption of *BBS7* orthologs in mice or macaques recapitulates many of the features of human patients, including retinal degeneration, abnormal renal morphology, and male reproductive defects (PMID: 23572516, PMID: 31589838). In summary, *BBS7* is definitively associated with BBS7-related ciliopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on September 7th, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0014435
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0014435
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014435
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014435
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0015229
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Gastrointestinal; Genitourinary; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic; Renal
Intervention: Cardiovascular; Endocrine
Rationale: Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management; Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial
Comments: Variants may modify the severity of BBS and related disorders due to variants in other BBS-associated genes
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BBS7 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_176824.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 7 | 168 | 1 | 176 | ||
| missense | 5 | 16 | 335 | 7 | 363 | |
| nonsense | 17 | 19 | 36 | |||
| start loss | 0 | |||||
| frameshift | 33 | 32 | 2 | 67 | ||
| splice donor/acceptor (+/-2bp) | 4 | 29 | 3 | 36 | ||
| Total | 59 | 96 | 347 | 175 | 1 | 678 |
Highest pathogenic variant AF is 0.000079356614
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_789794.1 | 19 | MANE Select | |
| Ensembl | ENSP00000264499.4 | 19 | MANE Select | |
| RefSeq | NP_060660.2 | 18 | Standard | |
| Ensembl | ENSP00000423626.1 | 18 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| bbs7 | Danio rerio | Structure: pronephric proximal convoluted tubule Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- BBSome-mediated cargo-targeting to cilium
- Cargo trafficking to the periciliary membrane
- Cilium Assembly
- Organelle biogenesis and maintenance
Biological Process
- eye development
- heart looping
- regulation of transcription by RNA polymerase II
- smoothened signaling pathway
- determination of left/right symmetry
Molecular Function
- RNA polymerase II repressing transcription factor binding
- protein binding
Cellular Component
- photoreceptor outer segment
- nucleus
- centrosome
- cytosol
- axoneme
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000264499
- Coding exons
- 19
- Length
- 46058
- Individuals with no LoFs
- 125607
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 140
- Defined
- 125747
- p
- 0.000557
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.23 | 307 | 374 | 0.821 | 0.0000181 | 4715 |
| Missense (PolyPhen) | 72 | 100.08 | 0.71941 | 1260 | ||
| Synonymous | 1.55 | 108 | 131 | 0.827 | 0.00000637 | 1326 |
| Loss of Function | 2.88 | 20 | 39.6 | 0.506 | 0.00000177 | 513 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00062 | 0.00062 | rare |
| Latino/Admixed American | 0.00038 | 0.00038 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00076 | 0.00076 | rare |
| Finnish | 0.00075 | 0.00074 | rare |
| European (Non-Finnish) | 0.00064 | 0.00063 | rare |
| South Asian | 0.00040 | 0.00039 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- 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. The BBSome complex, together with the LTZL1, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. Required for proper BBSome complex assembly and its ciliary localization. {ECO:0000269|PubMed:17574030, ECO:0000269|PubMed:22072986}.;
- Disease
- DISEASE: Bardet-Biedl syndrome 7 (BBS7) [MIM:615984]: A syndrome characterized by usually severe pigmentary retinopathy, early- onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. 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. {ECO:0000269|PubMed:12567324, ECO:0000269|PubMed:12677556, ECO:0000269|PubMed:15770229, ECO:0000269|PubMed:21344540}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.179
Intolerance Scores
- LoFtool
- 0.384
- RVIS EVS
- -0.4
- RVIS percentile EVS
- 26.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.311
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |