HPS6
protein-codingHPS6 biogenesis of lysosomal organelles complex 2 subunit 3, the group of Biogenesis of lysosomal organelles complex 2
Gene summary
This intronless 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 5 protein. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 6. [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 ~2.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013558
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013558
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013558
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0016502
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013558
Submitter: ClinGen
HPS6 was first reported in relation to autosomal recessive Hermansky-Pudlak syndrome (HPS) 6 in 2003 (Zhang Q, et al., 2003, PMID: 12548288). HPS is characterized by platelet dysfunction and oculocutaneous albinism, with diffuse hypopigmentation of the hair, skin, iris, and retina that leads to reduced visual acuity and nystagmus. Due to impaired platelet function, patients with HPS frequently suffer epistaxis or easy bruising, but might also experience more severe bleeding episodes, especially menorrhagia or postpartum bleeding. At least 39 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 4 publications (PMIDs: 12548288, 30387913, 19843503, 27917594). Variants in this gene segregated with disease in 1 additional family member (PMID: 27917594). 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 HPS5 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 cells (PMID: 19843503). Additionally the nop frog model (PMID: 27595926) and ruby-eye mouse model (PMID: 12548288) both recapitulate phenotypes of human HPS. In summary, HPS6 is definitively associated with autosomal recessive Hermansky-Pudlak syndrome 6. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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 HPS6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_024747.6. 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 | 14 | 191 | 1 | 206 | ||
| missense | 1 | 6 | 280 | 25 | 312 | |
| nonsense | 22 | 14 | 1 | 37 | ||
| start loss | 1 | 1 | 2 | |||
| frameshift | 31 | 31 | 3 | 65 | ||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 54 | 52 | 299 | 216 | 1 | 622 |
Highest pathogenic variant AF is 0.00008951629
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_079023.2 | 1 | MANE Select | |
| Ensembl | ENSP00000299238.5 | 1 | MANE Select |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- organelle organization
- blood coagulation
- melanocyte differentiation
- lysosome localization
- protein localization to membrane
Molecular Function
- protein binding
- Rab GTPase binding
- GTP-dependent protein binding
Cellular Component
- lysosomal membrane
- endoplasmic reticulum
- membrane
- BLOC-2 complex
- early endosome membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000299238
- Coding exons
- 1
- Length
- 2646
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0257 | 404 | 403 | 1.00 | 0.0000235 | 4748 |
| Missense (PolyPhen) | 108 | 127.6 | 0.84639 | 1637 | ||
| Synonymous | -1.65 | 220 | 191 | 1.15 | 0.0000103 | 1880 |
| Loss of Function | 2.61 | 10 | 23.7 | 0.421 | 0.00000160 | 209 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
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 (PubMed:17041891). Acts as cargo adapter for the dynein-dynactin motor complex to mediate the transport of lysosomes from the cell periphery to the perinuclear region. Facilitates retrograde lysosomal trafficking by linking the motor complex to lysosomes, and perinuclear positioning of lysosomes is crucial for the delivery of endocytic cargos to lysosomes, for lysosome maturation and functioning (PubMed:25189619). {ECO:0000269|PubMed:17041891, ECO:0000269|PubMed:25189619}.;
Recessive Scores
- pRec
- 0.149
Intolerance Scores
- LoFtool
- 0.341
- RVIS EVS
- -1.04
- RVIS percentile EVS
- 7.71
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.861
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |