BBS4

Bardet-Biedl syndrome 4, the group of BBSome|Tetratricopeptide repeat domain containing

Basic information

Region (hg38): 15:72686186-72742006

Links

ENSG00000140463 ∙ NCBI:585 ∙ OMIM:600374 ∙ HGNC:969 ∙ Uniprot:Q96RK4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Bardet-Biedl syndrome 4 (Definitive), mode of inheritance: AR
• Bardet-Biedl syndrome 4 (Strong), mode of inheritance: AR
• Bardet-Biedl syndrome (Supportive), mode of inheritance: AR
• Bardet-Biedl syndrome 4 (Strong), mode of inheritance: AR
• ciliopathy (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Bardet-Biedl syndrome 4	AR	Cardiovascular; Endocrine	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	Cardiovascular; Craniofacial; Gastrointestinal; Genitourinary; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic; Renal	7711739; 11381270; 12016587; 15654695; 20301537; 22219648; 36356613
Variants may modify the severity of BBS and related disorders due to variants in other BBS-associated genes

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the BBS4 gene.

• Bardet-Biedl syndrome (37 variants)
• Bardet-Biedl syndrome 4 (8 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the BBS4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	130	2	136
missense	2	3	160	3	2	170
nonsense	11	20	1			32
start loss		2	1			3
frameshift	16	31	4			51
inframe indel			5	1		6
splice donor/acceptor (+/-2bp)	7	21	2			30
splice region	2	5	13	29	1	50
non coding		3	29	119	19	170
Total	36	80	206	253	23

Highest pathogenic variant AF is 0.0000329

Variants in BBS4

This is a list of pathogenic ClinVar variants found in the BBS4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
15-72686190-C-A		not specified • Bardet-Biedl syndrome 4	Benign (Jan 12, 2018)
15-72686211-C-A		Bardet-Biedl syndrome	Benign (Oct 13, 2009)
15-72686211-C-T		not specified • Bardet-Biedl syndrome 4	Benign (Jan 13, 2018)
15-72686214-T-A		Bardet-Biedl syndrome 4	Uncertain significance (Jan 13, 2018)
15-72686220-G-C		BBS4-related disorder	Likely benign (Apr 17, 2019)
15-72686222-G-A		Bardet-Biedl syndrome	Benign (Oct 13, 2009)
15-72686225-A-G		Bardet-Biedl syndrome 4	Uncertain significance (Jan 06, 2022)
15-72686228-A-G		Bardet-Biedl syndrome • BBS4-related disorder	Pathogenic/Likely pathogenic (Dec 22, 2023)
15-72686229-T-C		Bardet-Biedl syndrome	Pathogenic/Likely pathogenic (Aug 17, 2023)
15-72686232-C-T		Bardet-Biedl syndrome	Uncertain significance (Apr 17, 2022)
15-72686233-T-A		Bardet-Biedl syndrome • BBS4-related disorder	Likely benign (Nov 27, 2023)
15-72686233-T-G		Bardet-Biedl syndrome	Likely benign (Feb 21, 2023)
15-72686235-A-C		Bardet-Biedl syndrome	Benign (Oct 13, 2009)
15-72686236-G-A		Bardet-Biedl syndrome	Likely benign (Dec 05, 2023)
15-72686237-G-A		Bardet-Biedl syndrome	Uncertain significance (Jul 12, 2022)
15-72686237-G-C		Bardet-Biedl syndrome	Uncertain significance (Jun 30, 2022)
15-72686237-G-T		Bardet-Biedl syndrome • Bardet-Biedl syndrome 4	Pathogenic/Likely pathogenic (Aug 10, 2023)
15-72686239-G-A		not specified • Bardet-Biedl syndrome	Likely benign (Dec 26, 2023)
15-72686241-G-C		Bardet-Biedl syndrome	Uncertain significance (Apr 26, 2022)
15-72686243-G-A		Bardet-Biedl syndrome	Uncertain significance (Mar 27, 2022)
15-72686244-T-C		Bardet-Biedl syndrome	Benign (Oct 13, 2009)
15-72686244-T-G		BBS4-related disorder	Uncertain significance (Sep 05, 2024)
15-72686245-C-A		Bardet-Biedl syndrome	Likely benign (Jul 29, 2023)
15-72686245-C-T		Bardet-Biedl syndrome	Benign (Oct 13, 2009)
15-72686246-G-A		Bardet-Biedl syndrome	Uncertain significance (Mar 18, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
BBS4	protein_coding	protein_coding	ENST00000268057	16	52291

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.45e-16	0.0440	125678	0	70	125748	0.000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.956	301	258	1.17	0.0000128	3375
Missense in Polyphen		77	76.661	1.0044		1009
Synonymous	-1.25	112	96.4	1.16	0.00000511	954
Loss of Function	0.735	27	31.4	0.858	0.00000146	398

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000564	0.000564
Ashkenazi Jewish	0.000198	0.000198
East Asian	0.000163	0.000163
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000309	0.000308
Middle Eastern	0.000163	0.000163
South Asian	0.000295	0.000294
Other	0.000815	0.000815

dbNSFP

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 proper BBSome complex assembly and its ciliary localization. Required for microtubule anchoring at the centrosome but not for microtubule nucleation. May be required for the dynein-mediated transport of pericentriolar proteins to the centrosome. {ECO:0000269|PubMed:15107855, ECO:0000269|PubMed:17574030, ECO:0000269|PubMed:22072986}.
• Pathway: Prader-Willi and Angelman Syndrome;BBSome-mediated cargo-targeting to cilium;Cargo trafficking to the periciliary membrane;Cilium Assembly;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.328

Intolerance Scores

• loftool: 0.571
• rvis_EVS: 0.11
• rvis_percentile_EVS: 62.1

Haploinsufficiency Scores

• pHI: 0.129
• hipred: N
• hipred_score: 0.415
• ghis: 0.513

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.921

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Bbs4
• Phenotype: taste/olfaction phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); craniofacial phenotype; immune system phenotype; homeostasis/metabolism phenotype; cellular phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system phenotype; embryo phenotype; pigmentation phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; reproductive system phenotype; vision/eye phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; renal/urinary system phenotype

Zebrafish Information Network

• Gene name: bbs4
• Affected structure: pancreatic B cell
• Phenotype tag: abnormal
• Phenotype quality: increased area

Gene ontology

• Biological process: microtubule cytoskeleton organization;mitotic cytokinesis;neuron migration;neural tube closure;retina homeostasis;heart looping;negative regulation of systemic arterial blood pressure;centrosome cycle;spermatid development;visual perception;sensory perception of smell;negative regulation of gene expression;protein transport;dendrite development;regulation of lipid metabolic process;ventricular system development;striatum development;hippocampus development;cerebral cortex development;adult behavior;negative regulation of actin filament polymerization;melanosome transport;regulation of cytokinesis;protein localization to organelle;negative regulation of GTPase activity;microtubule anchoring at centrosome;social behavior;photoreceptor cell outer segment organization;negative regulation of appetite by leptin-mediated signaling pathway;positive regulation of multicellular organism growth;fat cell differentiation;photoreceptor cell maintenance;positive regulation of cilium assembly;retinal rod cell development;intracellular transport;brain morphogenesis;sensory processing;maintenance of protein location in nucleus;regulation of stress fiber assembly;cilium assembly;regulation of cilium beat frequency involved in ciliary motility;face development;fat pad development;protein localization to cilium;protein localization to centrosome;regulation of non-motile cilium assembly;protein localization to photoreceptor outer segment;non-motile cilium assembly
• Cellular component: pericentriolar material;photoreceptor outer segment;photoreceptor inner segment;nucleus;centrosome;centriole;cytosol;cilium;motile cilium;photoreceptor connecting cilium;centriolar satellite;BBSome;ciliary transition zone;ciliary basal body;ciliary membrane;non-motile cilium
• Molecular function: RNA polymerase II repressing transcription factor binding;microtubule motor activity;protein binding;dynactin binding;alpha-tubulin binding;beta-tubulin binding