HPS1

protein-coding

HPS1 biogenesis of lysosomal organelles complex 3 subunit 1, the group of MicroRNA protein coding host genes|Biogenesis of lysosomal organelles complex 3

Gene summary

This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is a component of three different protein complexes termed biogenesis of lysosome-related organelles complex (BLOC)-3, BLOC4, and BLOC5. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 1. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on chromosome 22. [provided by RefSeq, Aug 2015]

Previous symbols:

MANE transcript

NM_000195.5

Inheritance

ClinVar variants

P:229U:326B:412

Top phenotype

Hermansky-Pudlak syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr10:98,410,939-98,446,963

External References & Databases

Ensembl (ENSG00000107521)

Transcript & Mutation Effects

hg38 • Region Span ~36.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Hermansky-Pudlak syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008748

Submitter: ClinGen

HPS1 was first reported in relation to Autosomal Recessive Hermasky-Pudlak syndrome 1 in 1996 (Oh et al., PMID: 8896559). At least 36 unique variants including missense, in-frame indel, nonsense, frameshift, and large deletions have been reported in humans. HPS1 is involved in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Hermansky-Pudlak syndrome 1 is characterized by severe oculocutaneous albinism and a bleeding diathesis, but in some cases, also pulmonary fibrosis and granulomatous colitis. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 12 Points Variants in this gene have been reported in at least 10 probands in 4 publications (PMIDs: 8896559, 9497254, 9705234, 27593200). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function (PMID: 9256466) Summary of Experimental Data: 5.5 Points This gene-disease association is supported by mouse models and in vitro functional assays. The "pale ear" or ep mouse that carries a spontaneously occurring mutation in Hps1 recapitulates the human HPS phenotype (PMID: 9256466, 9158155). HPS1 interacts with HPS4 to form BLOC-3, which is involved in the biogenesis of lysosome-related organelles (PMID: 12847290, 29190429, 25468649). In summary, HPS1 is definitively associated with Autosomal Recessive Hermasky-Pudlak syndrome 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on June 26, 2019 (SOP Version 6).

Hermansky-Pudlak syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008748

Submitter: Labcorp Genetics (formerly Invitae)

Hermansky-Pudlak syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008748

Submitter: G2P

Hermansky-Pudlak syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008748

Submitter: Natera

Hermansky-Pudlak syndrome with pulmonary fibrosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016501

Submitter: Orphanet

Hermansky-Pudlak syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008748

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hermansky-Pudlak syndrome 1AR

Manifestation: Allergy/Immunology/Infectious; Dermatologic; Gastrointestinal; Hematologic; Ophthalmologic; Pulmonary

Intervention: Allergy/Immunology/Infectious; Dermatologic; Gastrointestinal; Hematologic; Ophthalmologic; Pharmacogenomic; Pulmonary

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; Lung transplantation has been described

Refs: 3921802; 2916560; 8896559; 9562579; 9497254; 10411151; 10768343; 11414528; 12126938; 16210149; 19398212; 19729668; 20301464; 20514622; 20662851; 21833017

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HPS1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 1004

Hermansky-Pudlak syndrome 1Total: 362

Hermansky-Pudlak syndromeTotal: 177

Inborn genetic diseasesTotal: 116

not specifiedTotal: 105

HPS1-related disorderTotal: 63

HPS1-related disordersTotal: 13

Hermansky-Pudlak syndrome with pulmonary fibrosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000195.5. 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			6 clinvar	365 clinvar	2 clinvar	373
missense	1 clinvar	11 clinvar	318 clinvar	44 clinvar	1 clinvar	375
nonsense	39 clinvar	24 clinvar	1 clinvar			64
start loss		3 clinvar				3
frameshift	51 clinvar	52 clinvar				103
splice donor/acceptor (+/-2bp)	3 clinvar	45 clinvar	1 clinvar			49
Total	94	135	326	409	3	967

Highest pathogenic variant AF is 0.00032918024

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 201 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000195.5	RefSeq	NP_000186.2	18	MANE Select
ENST00000361490.9	Ensembl	ENSP00000355310.4	18	MANE Select
NM_001311345.2	RefSeq	NP_001298274.1	10	Standard
NM_001322476.2	RefSeq	NP_001309405.1	18	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Rab regulation of trafficking
RAB GEFs exchange GTP for GDP on RABs

Biological Process

lysosome organization
visual perception
response to stimulus
melanosome assembly

Molecular Function

guanyl-nucleotide exchange factor activity
protein binding
protein dimerization activity

Cellular Component

cytoplasm
lysosome
cytosol
BLOC-3 complex
cytoplasmic vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000325103
Coding exons: 18
Length: 30730
Individuals with no LoFs: 125671
Homozygous LoFs: 0
Heterozygous LoFs: 77
Defined: 125748
p: 0.000306

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.116	401	408	0.984	0.0000265	4511
Missense (PolyPhen)		151	151.46	0.99696		1765
Synonymous	-0.604	191	181	1.06	0.0000120	1425
Loss of Function	3.07	18	38.6	0.467	0.00000193	422

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00043	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00039	0.00038	rare
South Asian	0.00033	0.00033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the BLOC-3 complex, a complex that acts as a guanine exchange factor (GEF) for RAB32 and RAB38, promotes the exchange of GDP to GTP, converting them from an inactive GDP-bound form into an active GTP-bound form. The BLOC-3 complex plays an important role in the control of melanin production and melanosome biogenesis and promotes the membrane localization of RAB32 and RAB38 (PubMed:23084991). {ECO:0000269|PubMed:23084991}.;

Recessive Scores

pRec: 0.159

Intolerance Scores

LoFtool: 0.813
RVIS EVS: 0.85
RVIS percentile EVS: 88.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.637

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium