HPS4

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

Basic information

Region (hg38): 22:26443106-26483931

Links

ENSG00000100099 ∙ NCBI:89781 ∙ OMIM:606682 ∙ HGNC:15844 ∙ Uniprot:Q9NQG7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Hermansky-Pudlak syndrome 4 (Strong), mode of inheritance: AR
• Hermansky-Pudlak syndrome 4 (Moderate), mode of inheritance: AR
• Hermansky-Pudlak syndrome with pulmonary fibrosis (Supportive), mode of inheritance: AR
• Hermansky-Pudlak syndrome 4 (Definitive), mode of inheritance: AR
• Hermansky-Pudlak syndrome 4 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hermansky-Pudlak syndrome 4	AR	Allergy/Immunology/Infectious; Dermatologic; Gastrointestinal; Hematologic; Ophthalmologic; Pharmacogenomic; Pulmonary	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	Allergy/Immunology/Infectious; Dermatologic; Gastrointestinal; Hematologic; Ophthalmologic; Pulmonary	11836498; 20301464; 21833017

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HPS4 gene.

• not provided (420 variants)
• Hermansky-Pudlak syndrome 4 (163 variants)
• Hermansky-Pudlak syndrome (46 variants)
• Inborn genetic diseases (45 variants)
• not specified (44 variants)
• HPS4-related condition (2 variants)
• Albinism (2 variants)
• Oculocutaneous albinism (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HPS4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		1	7	103	2	113
missense		1	171	12	8	192
nonsense	5	12	2			19
start loss						0
frameshift	8	13		1		22
inframe indel			1			1
splice donor/acceptor (+/-2bp)		11				11
splice region			8	9		17
non coding		1	69	52	37	159
Total	13	39	250	168	47

Highest pathogenic variant AF is 0.0000263

Variants in HPS4

This is a list of pathogenic ClinVar variants found in the HPS4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
22-26443115-C-T		not specified	Uncertain significance (Dec 19, 2023)
22-26443117-C-T		not specified	Uncertain significance (Aug 21, 2023)
22-26443118-G-A		not specified	Uncertain significance (Aug 12, 2021)
22-26450964-T-C		Hermansky-Pudlak syndrome 4	Benign (Jan 12, 2018)
22-26451062-G-A		Hermansky-Pudlak syndrome 4	Uncertain significance (Jan 13, 2018)
22-26451271-G-A		Hermansky-Pudlak syndrome 4	Benign (Jan 13, 2018)
22-26451383-C-T		Hermansky-Pudlak syndrome 4	Likely benign (Jan 12, 2018)
22-26451471-C-T		Hermansky-Pudlak syndrome	Uncertain significance (Jun 14, 2016)
22-26451481-G-C		Hermansky-Pudlak syndrome 4	Uncertain significance (Jan 13, 2018)
22-26451542-C-T		Hermansky-Pudlak syndrome 4	Uncertain significance (Jan 13, 2018)
22-26451546-T-C		Hermansky-Pudlak syndrome 4	Benign (Jan 12, 2018)
22-26451620-G-T		Hermansky-Pudlak syndrome	Benign (Jun 14, 2016)
22-26451639-C-G		Hermansky-Pudlak syndrome 4	Uncertain significance (Jan 13, 2018)
22-26451644-G-T		Hermansky-Pudlak syndrome	Likely benign (Jun 14, 2016)
22-26451657-G-A		Hermansky-Pudlak syndrome 4	Uncertain significance (Jan 13, 2018)
22-26451705-A-C		Hermansky-Pudlak syndrome 4	Uncertain significance (Apr 27, 2017)
22-26451846-A-T		Hermansky-Pudlak syndrome 4	Benign (Apr 27, 2017)
22-26451874-T-A		Hermansky-Pudlak syndrome 4	Uncertain significance (Jan 13, 2018)
22-26451977-G-A		Hermansky-Pudlak syndrome 4	Uncertain significance (Jan 13, 2018)
22-26451980-C-T		Hermansky-Pudlak syndrome 4	Likely benign (Jan 12, 2018)
22-26451983-G-A		Hermansky-Pudlak syndrome 4	Benign (Jan 13, 2018)
22-26451986-ACG-A		Hermansky-Pudlak syndrome	Uncertain significance (Jun 14, 2016)
22-26451986-ACGCG-A		Hermansky-Pudlak syndrome	Uncertain significance (Jun 14, 2016)
22-26451986-ACGCGCG-A		Hermansky-Pudlak syndrome	Uncertain significance (Jun 14, 2016)
22-26451986-ACGCGCGCG-A		Hermansky-Pudlak syndrome	Uncertain significance (Jun 14, 2016)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HPS4	protein_coding	protein_coding	ENST00000398145	13	40415

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000138	1.00	125668	0	80	125748	0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.804	436	391	1.11	0.0000231	4580
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000770	0.000770
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000414	0.000413
Middle Eastern	0.000109	0.000109
South Asian	0.000137	0.000131
Other	0.000489	0.000489

dbNSFP

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.
• Pathway: Vesicle-mediated transport;Membrane Trafficking;Rab regulation of trafficking;RAB GEFs exchange GTP for GDP on RABs (Consensus)

Recessive Scores

• pRec: 0.224

Intolerance Scores

• loftool: 0.125
• rvis_EVS: 1.76
• rvis_percentile_EVS: 96.76

Haploinsufficiency Scores

• pHI: 0.104
• hipred: N
• hipred_score: 0.145
• ghis: 0.446

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.651

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hps4
• Phenotype: pigmentation phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; renal/urinary system phenotype; vision/eye phenotype; hearing/vestibular/ear phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype

Gene ontology

• Biological process: protein targeting;lysosome organization;blood coagulation;hemostasis;melanocyte differentiation;positive regulation of eye pigmentation;protein stabilization;melanosome assembly;positive regulation of protein targeting to mitochondrion
• Cellular component: cytoplasm;lysosome;cytosol;membrane;BLOC-3 complex;melanosome;platelet dense granule
• Molecular function: guanyl-nucleotide exchange factor activity;protein binding;Rab GTPase binding;protein homodimerization activity;protein dimerization activity