HPS4

protein-coding

HPS4 biogenesis of lysosomal organelles complex 3 subunit 2, the group of Biogenesis of lysosomal organelles complex 3

Gene summary

This gene encodes a protein component of biogenesis of lysosome-related organelles complexes (BLOC). BLOC complexes are important for the formation of endosomal-lysosomal organelles such as melanosomes and platelet dense granules. Mutations in this gene result in subtype 4 of Hermansky-Pudlak syndrome, a form of albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

MANE transcript

NM_022081.6

Inheritance

ClinVar variants

P:100U:260B:316

Top phenotype

Hermansky-Pudlak syndrome 4

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr22:26,443,107-26,483,931

External References & Databases

Ensembl (ENSG00000100099)

Transcript & Mutation Effects

hg38 • Region Span ~40.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Hermansky-Pudlak syndrome 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013556

Submitter: ClinGen

HPS4 was first reported in relation to Autosomal Recessive Hermasky-Pudlak syndrome 4 in 2002 (Suzuki et al., PMID: 11836498). At least 20 unique variants, mostly nonsense and frameshift, but also a few missense variants have been reported in humans. HPS4 is involved in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Hermansky-Pudlak syndrome 4 is characterized by 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 9 probands in 7 publications (PMIDs: 24433314, 15108212, 30990103, 30791930, 29108692, 11836498, 31415434). 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: 11836498). Summary of Experimental Data: 5 Points This gene-disease association is supported by animal models and in vitro functional assays. The "light ear" or le mouse that carries a spontaneously occurring mutation in Hps4 recapitulates the human HPS phenotype (PMID: 11836498). Another spontaneously occurring HPS4 mutation is identified to be the cause of albinism in channel catfish (PMID: 28289846). HPS4 interacts with HPS1 to form BLOC-3, which is involved in the biogenesis of lysosome-related organelles (PMID: 11836498, 23103514). In summary, HPS4 is definitively associated with Autosomal Recessive Hermasky-Pudlak syndrome 4. 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 May 27, 2020 (SOP Version 7).

Hermansky-Pudlak syndrome with pulmonary fibrosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016501

Submitter: Orphanet

Hermansky-Pudlak syndrome 4MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013556

Submitter: Ambry Genetics

Hermansky-Pudlak syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013556

Submitter: PanelApp Australia

Hermansky-Pudlak syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013556

Submitter: Labcorp Genetics (formerly Invitae)

Hermansky-Pudlak syndrome 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013556

Submitter: G2P

Clinical Genomic Database (CGD)

Hermansky-Pudlak syndrome 4AR

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

Refs: 11836498; 20301464; 21833017

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HPS4 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 700

Hermansky-Pudlak syndrome 4Total: 130

Inborn genetic diseasesTotal: 116

not specifiedTotal: 110

HPS4-related disorderTotal: 53

Hermansky-Pudlak syndromeTotal: 7

HPS4-related disordersTotal: 6

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022081.6. 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			2 clinvar	279 clinvar		281
missense		2 clinvar	253 clinvar	31 clinvar	6 clinvar	292
nonsense	15 clinvar	19 clinvar	2 clinvar			36
start loss						0
frameshift	17 clinvar	21 clinvar	2 clinvar			40
splice donor/acceptor (+/-2bp)	1 clinvar	25 clinvar	1 clinvar			27
Total	33	67	260	310	6	676

Highest pathogenic variant AF is 0.00011366149

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 122 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022081.6	RefSeq	NP_071364.4	13	MANE Select
ENST00000398145.7	Ensembl	ENSP00000381213.2	13	MANE Select
NM_001349896.1	RefSeq	NP_001336825.1	13	Standard
NM_001349898.2	RefSeq	NP_001336827.1	13	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

protein targeting
lysosome organization
blood coagulation
hemostasis
melanocyte differentiation

Molecular Function

guanyl-nucleotide exchange factor activity
protein binding
Rab GTPase binding
protein homodimerization activity
protein dimerization activity

Cellular Component

cytoplasm
lysosome
cytosol
membrane
BLOC-3 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000398145
Coding exons: 13
Length: 40415
Individuals with no LoFs: 125668
Homozygous LoFs: 0
Heterozygous LoFs: 80
Defined: 125748
p: 0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.804	436	391	1.11	0.0000231	4580
Missense (PolyPhen)		105	114.32	0.91846		1509
Synonymous	-2.64	210	167	1.26	0.0000108	1465
Loss of Function	3.13	12	30.7	0.391	0.00000141	367

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00052	0.00052	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00041	0.00041	rare
South Asian	0.00014	0.00013	rare
Other	0.00049	0.00049	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}.;
Disease: DISEASE: Hermansky-Pudlak syndrome 4 (HPS4) [MIM:614073]: A form of Hermansky-Pudlak syndrome, a genetically heterogeneous autosomal recessive disorder characterized by oculocutaneous albinism, bleeding due to platelet storage pool deficiency, and lysosomal storage defects. This syndrome results from defects of diverse cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes. Ceroid storage in the lungs is associated with pulmonary fibrosis, a common cause of premature death in individuals with HPS. {ECO:0000269|PubMed:11836498}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.224

Intolerance Scores

LoFtool: 0.125
RVIS EVS: 1.76
RVIS percentile EVS: 96.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.651

Gene Damage Prediction

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