BLOC1S5
protein-codingbiogenesis of lysosomal organelles complex 1 subunit 5, the group of Biogenesis of lysosomal organelles complex 1 subunits
Gene summary
This gene encodes a component of BLOC-1 (biogenesis of lysosome-related organelles complex 1). Components of this complex are involved in the biogenesis of organelles such as melanosomes and platelet-dense granules. A mouse model for Hermansky-Pudlak Syndrome is mutated in the murine version of this gene. Alternative splicing results in multiple transcript variants. Read-through transcription exists between this gene and the upstream EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) gene, as well as with the downstream TXNDC5 (thioredoxin domain containing 5) gene. [provided by RefSeq, Dec 2010]
- MUTED
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~50.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0030903
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0030903
Submitter: ClinGen
BLOC1S5 was first reported in relation to autosomal recessive Hermansky-Pudlak syndrome (HPS) 11 in 2020 (Pennamen et al, PMID: 32565547). Hermansky-Pudlak syndrome 11 is a subtype of Hermansky-Pudlak syndrome, characterized by oculocutaneous albinism, bleeding diathesis, and platelet dysfunction. BLOC1S5 encodes subunit 5 of the Biogenesis of Lysome-related Organelles Complex 1, BLOC-1, which is required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules (PMID: 15102850). Variants in 4 of the 8 subunits of BLOC-1 have been associated with HPS in humans (Li et al., 2003, PMID: 12923531; Morgen et al., 2006 PMID: 16385460; Badolato et al., 2012, PMID: 22461475; Pennamen et al., 2020, PMID: 32565547). Evidence supporting this gene-disease relationship includes case-level and experimental data. The mechanism of disease is expected to be biallelic loss of function. Summary of Case Level Data (9.5 points): Four variants (Nonsense, frameshift, canonical splicing, and multi exon deletion) in this gene have been reported in 4 probands in 3 publications (PMID: 32565547, 34685610, 34058075). A variant in this gene segregated with disease in 1 additional family member (PMID: 34685610). Summary of Experimental Data (4.25 points): This gene-disease association is supported by studies of protein interaction with other subunits of BLOC-1 (PMID: 12923531), mouse (muted) (PMID: 11912185) and zebrafish (PMID: 34058075) model systems that recapitulate the HPS phenotype, and rescue models in mouse melanocytes (PMID: 32565547). In summary, BLOC1S5 is definitively associated with autosomal recessive Hermansky-Pudlak syndrome 11. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has held up over time.
Inheritance Pattern: AR
Disease ID:MONDO:0019312
Submitter: Franklin by Genoox
Two unrelated patients with distinct homozygous variants of the BLOC1S5 gene and clincal signs compatible with HPS . Functional studies support the connection. https://www.nature.com/articles/s41436-020-0867-5
Inheritance Pattern: AR
Disease ID:MONDO:0030903
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0030903
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Dermatologic; Hematologic; Ophthalmologic
Intervention: Allergy/Immunology/Infectious; Dermatologic; Hematologic; Ophthalmologic
Rationale: Prevention and treatment of bleeding episodes (eg, with DDAVP or platelet/RBC transfusions) can be effective, and aspirin-containing products should be avoided; Skin surveillance and protection can be beneficial; Surveillance related to ophthalmologic and other manifestations has been recommended in all individuals with HPS
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BLOC1S5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_201280.3. 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 | 3 | 3 | ||||
| missense | 39 | 4 | 43 | |||
| nonsense | 2 | 2 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | 2 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 2 | 4 | 39 | 7 | 0 | 52 |
Highest pathogenic variant AF is 0.000010540793
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_958437.1 | 5 | MANE Select | |
| Ensembl | ENSP00000380598.2 | 5 | MANE Select | |
| RefSeq | NP_001186251.1 | 4 | Standard | |
| RefSeq | NP_001186252.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- anterograde axonal transport
- neuron projection development
- melanosome transport
- melanosome organization
- endosome to melanosome transport
Molecular Function
- protein binding
Cellular Component
- transport vesicle
- BLOC-1 complex
- axon cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000397457
- Coding exons
- 5
- Length
- 50848
- Individuals with no LoFs
- 125670
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 76
- Defined
- 125747
- p
- 0.000306
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.250 | 109 | 102 | 1.07 | 0.00000505 | 1244 |
| Missense (PolyPhen) | 28 | 25.941 | 1.0794 | 345 | ||
| Synonymous | -0.274 | 35 | 33.0 | 1.06 | 0.00000150 | 325 |
| Loss of Function | -0.569 | 12 | 10.1 | 1.19 | 5.89e-7 | 114 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.0012 | 0.0011 | notable |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00039 | 0.00038 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00021 | 0.00021 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00018 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals. The BLOC-1 complex, in association with SNARE proteins, is also proposed to be involved in neurite extension. Plays a role in intracellular vesicle trafficking. {ECO:0000269|PubMed:17182842}.;
Recessive Scores
- pRec
- 0.258
Intolerance Scores
- RVIS EVS
- -0.21
- RVIS percentile EVS
- 38.58
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |