# NM_152384.3(BBS5):c.265C>T (p.Arg89Ter)

https://sugi.bio/variant/bbs5-p-arg89ter

## Summary

**BBS5 p.Arg89Ter (c.265C>T)** is classified **Pathogenic** in BBS5 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-23). Very rare (popmax 0.00223%, eas); Associated with Bardet-Biedl syndrome 5.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs772757329 · 6 submitters · 2 linked conditions · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the BBS5 gene that is considered disease-causing, submitted by 6 submitters, and is linked to Bardet-Biedl syndrome 5.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive, Oligogenic |
| Age of onset (of this condition) | Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Specific population) |
| Diagnostic panels | BBS5 is a diagnostic-grade gene on 17 Genomics England panels |

**Commonly reported features of Bardet-Biedl syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Retinal dystrophy — Obligate (100%)
- Cone/cone-rod dystrophy — Very frequent (99-80%)
- Obesity — Very frequent (99-80%)
- Childhood-onset truncal obesity — Very frequent (99-80%)
- Neurodevelopmental delay — Very frequent (99-80%)
- Abnormality of the genitourinary system — Frequent (79-30%)
- Hypogonadism — Frequent (79-30%)
- Abnormal oral cavity morphology — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010204/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BBS5](https://sugi.bio/atlas/gene/BBS5/) |
| Protein change (HGVS p.) | p.Arg89Ter |
| Coding change (HGVS c.) | c.265C>T |
| MANE Select transcript | [NM_152384](https://www.ncbi.nlm.nih.gov/nuccore/NM_152384) |
| dbSNP | [rs772757329](https://www.ncbi.nlm.nih.gov/snp/rs772757329/) |
| Variant type | single nucleotide variant |
| Location | chr2:169487993-169487993 (GRCh38) |
| ClinVar | [VCV531823](https://www.ncbi.nlm.nih.gov/clinvar/variation/531823/) |

**All HGVS expressions:** `NC_000002.11:g.170344503C>T`, `NC_000002.12:g.169487993C>T`, `NG_011567.1:g.13498C>T`, `NM_152384.3:c.265C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.23) — consistent with the pathogenic call
- Conservation: phyloP 3.202, GERP 1.56, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.884, pLI 0.00025273. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 12**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 40.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.23**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 6 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.28** (loss), gain 0.01 / loss 0.28. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 0.000615% · FAF99 0.000474% · 1/44,818 in the highest group · 16/1,613,378 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,818 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,462 |
| African / African-American | 0.00134% | 74,870 |
| European (non-Finnish) | 0.0011% | 90,743 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**BBS5** population constraint: LOEUF 0.884, pLI 0.00025273, missense-Z 1.0111; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **BBS5-related ciliopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.87, 73% of residues very-high.

**1 experimental structure(s)** (PDB): [6XTB](https://www.rcsb.org/structure/6XTB).

## What this gene does {#gene-function}

*Describes the biological roles of BBS5 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BBS5's established molecular role includes phosphatidylinositol-3-phosphate binding.


### Pathways affected {#pathways}

BBS5 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [BBSome-mediated cargo-targeting to cilium](https://reactome.org/content/detail/R-HSA-5620922) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** phosphatidylinositol-3-phosphate binding, RNA polymerase II-specific DNA-binding transcription factor binding.

**Biological process:** cilium assembly.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-23.

**Submitter consensus:** unanimous (6/6 Pathogenic).

**Submission history:** 6 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Johns Hopkins Genomics, Johns Hopkins University | Pathogenic | criteria provided, single submitter | clinical testing | 2020-01-18 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-30 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-02-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-23 |
| Lab De Baere, Eye and Developmental Genetics Lab, Ghent University | Pathogenic | criteria provided, single submitter | research | 2024-10-01 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-26 |

## Associated conditions {#conditions}

[Bardet-Biedl syndrome 5](https://sugi.bio/atlas/disease/bardet-biedl-syndrome-5/), [Bardet-Biedl syndrome](https://sugi.bio/atlas/disease/bardet-biedl-syndrome/).

**Reported phenotype names (ClinVar):** Bardet-Biedl syndrome 5, Bardet-Biedl syndrome, not provided, BBS5-related disorder, BBS5-related condition, none provided.

## Similar variants {#similar}

Related BBS5 variant pages (same residue, condition, or type): [BBS5 p.Arg89Gln](/variant/bbs5-p-arg89gln), [BBS5 c.143-1G>C](/variant/bbs5-c-143-minus-1g-c), [BBS5 c.209-1G>A](/variant/bbs5-c-209-minus-1g-a), [BBS5 c.209-2A>G](/variant/bbs5-c-209-minus-2a-g), [BBS5 c.522+3A>G](/variant/bbs5-c-522-plus-3a-g), [BBS5 c.681+1G>T](/variant/bbs5-c-681-plus-1g-t), [BBS5 p.Arg138Cys](/variant/bbs5-p-arg138cys), [BBS5 p.Arg138His](/variant/bbs5-p-arg138his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 531823). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*