HPS5
protein-codingHPS5 biogenesis of lysosomal organelles complex 2 subunit 2, the group of Biogenesis of lysosomal organelles complex 2 |WD repeat domain containing
Gene summary
This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. This protein interacts with Hermansky-Pudlak syndrome 6 protein and may interact with the cytoplasmic domain of integrin, alpha-3. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 5. Multiple transcript variants encoding two distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~43.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013557
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013557
Submitter: ClinGen
HPS5 was first reported with autosomal recessive Hermansky-Pudlak syndrome (HPS) 5 in 2003 (Zhang Q, et al., 2003, PMID: 12548288). HPS5 is characterized by oculocutaneous albinism, a bleeding diathesis, and lack of platelet dense bodies. HPS5 appears to be a milder form of the syndrome because the complications present in other forms of HPS, such as pulmonary fibrosis, granulomatous colitis, and neutropenia, have not been reported in HPS5 patients. At least 43 unique variants, including missense, nonsense, splice site, frameshift, and large deletions, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been curated for 8 probands in 7 publications (PMIDs: 26785811, 12548288, 23607980, 18182080, 29090612, 21833017, 15296495, ). More evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. This gene-disease relationship is supported by its interaction with HPS6 in the BLOC-2 complex (PMID: 12548288), which has a biochemical function in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes (PMID: 26008744), as well as the functional alteration, observed in patient fibroblast cells (PMID: 15296495). Additionally, the Zebrafish model (PMID: 23893484) and ruby-eye mouse model (PMID: 12548288) both recapitulate phenotypes of human HPS. In summary, HPS5 is definitively associated with autosomal recessive Hermansky-Pudlak syndrome 5. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0016502
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013557
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013557
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Dermatologic; Gastrointestinal; Hematologic; Ophthalmologic; Pulmonary
Intervention: Allergy/Immunology/Infectious; Dermatologic; Gastrointestinal; 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; Prompt treatment of pulmonary infections (as well as avoidance of cigarette smoke) to maximize pulmonary function is indicated, including influenza and pneumococcus vaccination; Surveillance related to ophthalmologic, gastrointestinal, and other manifestations has been recommended in all individuals with HPS
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HPS5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_181507.2. 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 | 2 | 8 | 283 | 1 | 294 | |
| missense | 1 | 4 | 350 | 25 | 1 | 381 |
| nonsense | 31 | 8 | 39 | |||
| start loss | 0 | |||||
| frameshift | 46 | 13 | 59 | |||
| splice donor/acceptor (+/-2bp) | 7 | 29 | 1 | 37 | ||
| Total | 87 | 54 | 359 | 308 | 2 | 810 |
Highest pathogenic variant AF is 0.00021502738
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_852608.1 | 22 | MANE Select | |
| Ensembl | ENSP00000265967.5 | 22 | MANE Select | |
| RefSeq | NP_001427831.1 | 23 | Standard | |
| RefSeq | NP_001427832.1 | 23 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| hps5 | Danio rerio | Structure: iridophore Quality: absent abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- organelle organization
- blood coagulation
- pigmentation
Molecular Function
- protein binding
Cellular Component
- BLOC-2 complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000349215
- Coding exons
- 22
- Length
- 43523
- Individuals with no LoFs
- 125627
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 121
- Defined
- 125748
- p
- 0.000481
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0640 | 585 | 589 | 0.993 | 0.0000297 | 7397 |
| Missense (PolyPhen) | 197 | 230.94 | 0.85302 | 2959 | ||
| Synonymous | 0.349 | 209 | 216 | 0.970 | 0.0000110 | 2157 |
| Loss of Function | 3.17 | 30 | 55.5 | 0.540 | 0.00000258 | 729 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00049 | 0.00049 | rare |
| Latino/Admixed American | 0.00049 | 0.00049 | rare |
| Ashkenazi Jewish | 0.0018 | 0.0018 | notable |
| East Asian | 0.00065 | 0.00065 | rare |
| Finnish | 0.00056 | 0.00055 | rare |
| European (Non-Finnish) | 0.00037 | 0.00037 | rare |
| South Asian | 0.00036 | 0.00036 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May regulate the synthesis and function of lysosomes and of highly specialized organelles, such as melanosomes and platelet dense granules. Regulates intracellular vesicular trafficking in fibroblasts. May be involved in the regulation of general functions of integrins. {ECO:0000269|PubMed:15296495, ECO:0000269|PubMed:17301833}.;
Recessive Scores
- pRec
- 0.187
Intolerance Scores
- LoFtool
- 0.963
- RVIS EVS
- 0.19
- RVIS percentile EVS
- 66.27
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.837
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |