HPS3

protein-coding

HPS3 biogenesis of lysosomal organelles complex 2 subunit 1, the group of Biogenesis of lysosomal organelles complex 2

Gene summary

This gene encodes a protein containing a potential clathrin-binding motif, consensus dileucine signals, and tyrosine-based sorting signals for targeting to vesicles of lysosomal lineage. The encoded protein may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 3. [provided by RefSeq, Apr 2015]

MANE transcript

NM_032383.5

Inheritance

ClinVar variants

P:380U:381B:439

Top phenotype

Hermansky-Pudlak syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr3:149,129,638-149,173,732

External References & Databases

Ensembl (ENSG00000163755)

Transcript & Mutation Effects

hg38 • Region Span ~44.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Hermansky-Pudlak syndrome without pulmonary fibrosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016502

Submitter: Orphanet

Hermansky-Pudlak syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013555

Submitter: ClinGen

The relationship between HPS3 and Hermasky-Pudlak syndrome 3, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of August 8, 2019. HPS3 was first reported in relation to Hermasky-Pudlak syndrome 3 in 2001 (Anikster, 2001, PMID: 11455388; Huizing, 2001, PMID: 11590544). At least 19 unique variants including nonsense, splice site, frameshift and large deletions have been reported in humans. Missense variants are not very common. HPS3 is involved in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Hermansky-Pudlak syndrome 3 is characterized by a mild phenotype compared to HPS1, with minimal hypopigmentation, ocular rather than oculocutaneous albinism and a mild bleeding diathesis (PMID: 20301464). It is generally not associated with pulmonary fibrosis or granulomatous colitis. Evidence supporting this gene-disease relationship includes case-level data, family data and experimental data. Summary of Case Level Data: 12 Points Variants in this gene have been reported in at least 7 probands in 5 publications (PMID: 11455388, 11590544, 28284561, 27593200, 30791930). Variants in the gene segregated with 4 additional family members (PMID: 11455388). 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: 20301464) Summary of Experimental Data: 5 Points This gene-disease association is supported by mouse models and in vitro functional assays. The "cocoa" or "coa" mouse that carries at least 4 diferent spontaneously occurring mutations in the mouse Hps3 gene recapitulates the human HPS phenotype (PMID: 11707070, 14718540). HPS3 interacts with HPS5 and HPS6 to form BLOC-2, which is involved in the biogenesis of lysosome-related organelles (PMID: 15675963, 15632015, 15030569, 14718540). In summary, HPS3 is definitively associated with autosomal recessive Hermasky-Pudlak syndrome 3. 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 February 26, 2020 (SOP Version 6).

Hermansky-Pudlak syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013555

Submitter: PanelApp Australia

Hermansky-Pudlak syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013555

Submitter: G2P

Hermansky-Pudlak syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013555

Submitter: Labcorp Genetics (formerly Invitae)

Hermansky-Pudlak syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013555

Submitter: Natera

Clinical Genomic Database (CGD)

Hermansky-Pudlak syndrome 3AR

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

Refs: 11455388; 20301464

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HPS3 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 1068

Hermansky-Pudlak syndrome 3Total: 346

Hermansky-Pudlak syndromeTotal: 186

Inborn genetic diseasesTotal: 140

not specifiedTotal: 79

HPS3-related disorderTotal: 38

HPS3-related disordersTotal: 7

ThrombocytopeniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032383.5. 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			14 clinvar	414 clinvar	1 clinvar	429
missense		3 clinvar	357 clinvar	22 clinvar	2 clinvar	384
nonsense	55 clinvar	55 clinvar				110
start loss	1 clinvar	1 clinvar	1 clinvar			3
frameshift	129 clinvar	95 clinvar	2 clinvar			226
splice donor/acceptor (+/-2bp)	7 clinvar	34 clinvar	7 clinvar			48
Total	192	188	381	436	3	1200

Highest pathogenic variant AF is 0.000099185905

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032383.5	RefSeq	NP_115759.2	17	MANE Select
ENST00000296051.7	Ensembl	ENSP00000296051.2	17	MANE Select
NM_001308258.2	RefSeq	NP_001295187.1	16	Standard
ENST00000460120.5	Ensembl	ENSP00000418230.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

organelle organization
pigmentation

Molecular Function

protein binding

Cellular Component

cytoplasm
BLOC-2 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296051
Coding exons: 17
Length: 44149
Individuals with no LoFs: 125593
Homozygous LoFs: 0
Heterozygous LoFs: 155
Defined: 125748
p: 0.000616

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.160	525	535	0.981	0.0000277	6529
Missense (PolyPhen)		263	276.53	0.95107		3491
Synonymous	-0.378	215	208	1.03	0.0000110	1927
Loss of Function	1.44	38	48.9	0.778	0.00000239	641

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00062	0.00062	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.0018	0.0018	notable
East Asian	0.0016	0.0016	notable
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00050	0.00050	rare
South Asian	0.0010	0.0010	notable
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in early stages of melanosome biogenesis and maturation. {ECO:0000250|UniProtKB:Q91VB4}.;

Recessive Scores

pRec: 0.164

Intolerance Scores

LoFtool: 0.961
RVIS EVS: -1.28
RVIS percentile EVS: 5.13

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.128

Gene Damage Prediction

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