BBS5

protein-coding

Bardet-Biedl syndrome 5, the group of BBSome

Gene summary

This gene encodes a protein that has been directly linked to Bardet-Biedl syndrome. The primary features of this syndrome include retinal dystrophy, obesity, polydactyly, renal abnormalities and learning disabilities. Experimentation in non-human eukaryotes suggests that this gene is expressed in ciliated cells and that it is required for the formation of cilia. Alternate transcriptional splice variants have been observed but have not been fully characterized. [provided by RefSeq, Jul 2008]

MANE transcript

NM_152384.3

Inheritance

ClinVar variants

P:77U:163B:104

Top phenotype

Bardet-Biedl syndrome 5

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr2:169,479,480-169,506,655

External References & Databases

Ensembl (ENSG00000163093)

Transcript & Mutation Effects

hg38 • Region Span ~27.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bardet-Biedl syndrome 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014434

Submitter: Ambry Genetics

Bardet-Biedl syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015229

Submitter: Orphanet

Bardet-Biedl syndrome 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014434

Submitter: Genomics England PanelApp

Bardet-Biedl syndrome 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014434

Submitter: G2P

Bardet-Biedl syndrome 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014434

Submitter: Labcorp Genetics (formerly Invitae)

Bardet-Biedl syndrome 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014434

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Bardet-Biedl syndrome 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014434

Submitter: PanelApp Australia

Bardet-Biedl syndrome 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014434

Submitter: Natera

BBS5-related ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:1040047

Submitter: ClinGen

*BBS5* was first reported in relation to autosomal recessive Bardet-Biedl syndrome (BBS) in 2004 (Li et al., PMID: 15137946). BBS is a rare genetically heterogeneous ciliopathy, characterized by rod-cone dystrophy, polydactyly, obesity, genital anomalies, renal anomalies, and intellectual disabilities. For the purposes of this gene curation, cases caused by biallelic variants in the *BBS5* gene have been curated under the broader disease term BBS5-related ciliopathy. This curation includes five variants (one missense, two frameshift, and two disrupting splicing) that have been reported in four probands. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by animal models indicating that loss of the *BBS5* ortholog recapitulates human patient features such as obesity, aberrant glucose homeostasis, and retinal abnormalities (PMIDs: 24559376, 31506453, 33560420). In summary, there is definitive evidence supporting the relationship between *BBS5* and autosomal recessive BBS5-related ciliopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Retina GCEP on the meeting date December 7th, 2023 (SOP Version 10).

Clinical Genomic Database (CGD)

Bardet-Biedl syndrome 5AR

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

Refs: 15137946; 18203199; 20301537; 22410627; 25982971; 36356613

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BBS5 variants in ClinVar

13 Conditions Cataloged

Bardet-Biedl syndromeTotal: 341

BBS5-related disorderTotal: 161

Bardet-Biedl syndrome 5Total: 103

not providedTotal: 61

not specifiedTotal: 40

Inborn genetic diseasesTotal: 34

Retinal dystrophyTotal: 3

Cone dystrophyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152384.3. 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			5 clinvar	91 clinvar	4 clinvar	100
missense	2 clinvar	8 clinvar	153 clinvar	7 clinvar	1 clinvar	171
nonsense	11 clinvar	6 clinvar	1 clinvar			18
start loss	3 clinvar	2 clinvar				5
frameshift	10 clinvar	13 clinvar	2 clinvar			25
splice donor/acceptor (+/-2bp)	4 clinvar	18 clinvar	2 clinvar	1 clinvar		25
Total	30	47	163	99	5	344

Highest pathogenic variant AF is 0.00003358092

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152384.3	RefSeq	NP_689597.1	12	MANE Select
ENST00000295240.8	Ensembl	ENSP00000295240.3	12	MANE Select
ENST00000392663.6	Ensembl	ENSP00000376431.2	11	Standard
ENST00000392663.7	Ensembl	ENSP00000376431.2	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
bbs5	Danio rerio	Structure: cloaca Quality: cystic abnormal

Gene / Model

Organism

Observed Phenotype

bbs5

Danio rerio

Structure: cloaca

Quality: cystic

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

heart looping
visual perception
protein transport
melanosome transport
motile cilium assembly

Molecular Function

RNA polymerase II repressing transcription factor binding
protein binding
phosphatidylinositol-3-phosphate binding

Cellular Component

cytosol
axoneme
centriolar satellite
BBSome
ciliary basal body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000295240
Coding exons: 12
Length: 46745
Individuals with no LoFs: 125684
Homozygous LoFs: 0
Heterozygous LoFs: 64
Defined: 125748
p: 0.000255

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.850	148	180	0.822	0.00000876	2239
Missense (PolyPhen)		95	110.68	0.85836		1429
Synonymous	1.07	50	60.6	0.825	0.00000300	610
Loss of Function	1.95	12	21.8	0.550	0.00000102	272

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00034	0.00033	rare
South Asian	0.000066	0.000065	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

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 BBSome complex ciliary localization but not for the proper complex assembly. {ECO:0000269|PubMed:17574030, ECO:0000269|PubMed:22072986}.;
Disease: DISEASE: Bardet-Biedl syndrome 5 (BBS5) [MIM:615983]: 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:15137946, ECO:0000269|PubMed:18203199, ECO:0000269|PubMed:21344540}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.225

Intolerance Scores

LoFtool: 0.595
RVIS EVS: 0.04
RVIS percentile EVS: 56.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.252