BLOC1S6

protein-coding

biogenesis of lysosomal organelles complex 1 subunit 6, the group of Biogenesis of lysosomal organelles complex 1 subunits

Gene summary

The protein encoded by this gene may play a role in intracellular vesicle trafficking. It interacts with Syntaxin 13 which mediates intracellular membrane fusion. Mutations in this gene cause symptoms associated with Hermansky-Pudlak syndrome-9. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on the X chromosome. [provided by RefSeq, Aug 2015]

Previous symbols:

PA
PLDN

MANE transcript

NM_012388.4

Inheritance

ClinVar variants

P:30U:72B:52

Top phenotype

Hermansky-Pudlak syndrome 9

gnomAD constraint

pLI —, LoF o/e 1.07

Max pathogenic AF

—

Genomic locus

chr15:45,587,214-45,615,945

External References & Databases

Ensembl (ENSG00000104164)

Transcript & Mutation Effects

hg38 • Region Span ~28.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Hermansky-Pudlak syndrome 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013606

Submitter: PanelApp Australia

Hermansky-Pudlak syndrome 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013606

Submitter: Labcorp Genetics (formerly Invitae)

Hermansky-Pudlak syndrome 9DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013606

Submitter: ClinGen

*BLOC1S6* was first reported in relation to autosomal recessive Hermansky-Pudlak syndrome 9 in 2012 (Badolato et al., PMID: 22461475). Hermansky-Pudlak syndrome 9 is a subtype of HPS, characterized by oculocutaneous albinism and platelet dysfunction. *BLOC1S6* encodes the coiled-coil-forming protein, Pallidin, a subunit of the Biogenesis of Lysosome-related Organelles Complex 1, BLOC-1, which is required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules (PMID: 15102850). Of the 8 subunits of BLOC-1, mutations in three, including BLOC1S6, are reported in association with HPS subtypes in humans (Huizing et al., Hermansky-Pudlak Syndrome, GeneReviews). Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of Case Level Data (9 points): Six variants (nonsense, frameshift, and missense) in this gene have been reported in at least 5 probands in 5 publications (PMID: 22461475, 29054114, 26575419, 32245340, 33543539). The mechanism for disease is expected to be biallelic loss of function. Summary of Experimental Data (3 points): This gene-disease association is supported by studies of protein interaction with other subunits of BLOC-1 and by the spontaneously occurring mouse mutation, “pallid” that recapitulates the HPS phenotype. In summary, *BLOC1S6* is definitively associated with autosomal recessive Hermansky-Pudlak syndrome 9. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the HT GCEP on 09/23/2020. It was reevaluated on 05/25/2022. As a result of this reevaluation, the classification changed from Moderate to Definitive due to a new case report (PMID: 33543539).

Hermansky-Pudlak syndrome 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013606

Submitter: G2P

Clinical Genomic Database (CGD)

Hermansky-Pudlak syndrome 9AR

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

Intervention: Allergy/Immunology/Infectious; Dermatologic; 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; Surveillance related to ophthalmologic and other manifestations has been recommended in all individuals with HPS

Refs: 21665000; 20301464; 22461475

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BLOC1S6 variants in ClinVar

7 Conditions Cataloged

Hermansky-Pudlak syndrome 9Total: 178

Inborn genetic diseasesTotal: 30

not specifiedTotal: 21

not providedTotal: 18

BLOC1S6-related disorderTotal: 11

Hermansky-Pudlak syndromeTotal: 3

Autoinflammatory syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012388.4. 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			1 clinvar	48 clinvar		49
missense		1 clinvar	64 clinvar	4 clinvar		69
nonsense	5 clinvar	1 clinvar	2 clinvar			8
start loss		1 clinvar	1 clinvar			2
frameshift	10 clinvar	3 clinvar	4 clinvar			17
splice donor/acceptor (+/-2bp)	2 clinvar	7 clinvar				9
Total	17	13	72	52	0	154

Highest pathogenic variant AF is 0.000013150628

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012388.4	RefSeq	NP_036520.1	5	MANE Select
ENST00000220531.9	Ensembl	ENSP00000220531.4	5	MANE Select
NM_001311255.1	RefSeq	NP_001298184.1	5	Standard
NM_001311256.1	RefSeq	NP_001298185.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Golgi Associated Vesicle Biogenesis
Clathrin derived vesicle budding
trans-Golgi Network Vesicle Budding
Vesicle-mediated transport
Membrane Trafficking

Biological Process

anterograde axonal transport
synaptic vesicle docking
neuron projection development
melanosome transport
melanosome organization

Molecular Function

protein binding
syntaxin binding
identical protein binding
protein homodimerization activity
actin filament binding

Cellular Component

cytoplasm
cytosol
extrinsic component of membrane
transport vesicle
BLOC-1 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000220531
Coding exons: 5
Length: 28877
Individuals with no LoFs: 125715
Homozygous LoFs: 0
Heterozygous LoFs: 27
Defined: 125742
p: 0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.859	64	86.5	0.740	0.00000386	1115
Missense (PolyPhen)		30	36.06	0.83195		512
Synonymous	0.132	32	33.0	0.971	0.00000146	307
Loss of Function	-0.211	12	11.2	1.07	6.71e-7	130

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0.00029	0.00029	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals. The BLOC-1 complex, in association with SNARE proteins, is also proposed to be involved in neurite extension. May play a role in intracellular vesicle trafficking, particularly in the vesicle-docking and fusion process. {ECO:0000269|PubMed:17182842, ECO:0000269|PubMed:21998198}.;
Disease: DISEASE: Hermansky-Pudlak syndrome 9 (HPS9) [MIM:614171]: 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:21665000}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.232

Intolerance Scores

RVIS EVS: 0.13
RVIS percentile EVS: 62.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N

Gene Damage Prediction

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