BBS4

Chr 15AR

Bardet-Biedl syndrome 4

NCBI Gene: 585 ENSG00000140463 UniProt: Q96RK4 OMIM: 615982

This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse. The similar phenotypes exhibited by mutations in BBS gene family members are likely due to the protein's shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene has sequence similarity to O-linked N-acetylglucosamine (O-GlcNAc) transferases in plants and archaebacteria and in human forms a multi-protein "BBSome" complex with seven other BBS proteins. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.182 OMIM phenotypes

Clinical Summary— BBS4

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Gene-Disease Validity (ClinGen)

BBS4-related ciliopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

182 unique Pathogenic / Likely Pathogenic· 318 VUS of 929 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — BBS4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.18LOEUF

pLI 0.000

Z-score 0.74

OE 0.86 (0.63–1.18)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.96Z-score

OE missense 1.17 (1.06–1.28)

301 obs / 257.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.86 (0.63–1.18)

0≤0.351.4

Missense OE?1.17 (1.06–1.28)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 27 / 31.5Missense obs/exp: 301 / 257.8Syn Z: -1.25

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveBBS4-related Bardet-Biedl syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6258th %ile

GOF

0.6639th %ile

LOF

0.4038th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

929 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic74

Likely Pathogenic108

VUS318

Likely Benign339

Benign32

Conflicting36

Pathogenic

108

Likely Pathogenic

318

VUS

339

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	46	3	25	0	74
Likely Pathogenic	99	6	3	0	108
VUS	6	263	42	7	318
Likely Benign	1	4	170	164	339
Benign	1	5	23	3	32
Conflicting	—				36
Total	153	281	263	174	907

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

36 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap BBS4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →