BLOC1S5

Chr 6AR

biogenesis of lysosomal organelles complex 1 subunit 5

Also known as: BLOS5, HPS11, MU, MUTED

NCBI Gene: 63915 ENSG00000188428 UniProt: Q8TDH9 OMIM: 607289

The protein functions as a component of the BLOC-1 complex, which is required for normal biogenesis of lysosome-related organelles such as platelet dense granules and melanosomes, and targets membrane protein cargos into vesicles for delivery to neurites and nerve terminals. Mutations cause Hermansky-Pudlak syndrome 11, inherited in an autosomal recessive pattern. The disease mechanism involves loss of function, consistent with the requirement for functional BLOC-1 complex assembly.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a component of BLOC-1 (biogenesis of lysosome-related organelles complex 1). Components of this complex are involved in the biogenesis of organelles such as melanosomes and platelet-dense granules. A mouse model for Hermansky-Pudlak Syndrome is mutated in the murine version of this gene. Alternative splicing results in multiple transcript variants. Read-through transcription exists between this gene and the upstream EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) gene, as well as with the downstream TXNDC5 (thioredoxin domain containing 5) gene. [provided by RefSeq, Dec 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.811 OMIM phenotype

Clinical Summary— BLOC1S5

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Gene-Disease Validity (ClinGen)

Hermansky-Pudlak syndrome 11 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

7 unique Pathogenic / Likely Pathogenic· 39 VUS of 56 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — BLOC1S5

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.81LOEUF

pLI 0.000

Z-score -0.57

OE 1.19 (0.76–1.81)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.25Z-score

OE missense 1.07 (0.92–1.25)

109 obs / 101.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.19 (0.76–1.81)

0≤0.351.4

Missense OE?1.07 (0.92–1.25)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 12 / 10.1Missense obs/exp: 109 / 101.9Syn Z: -0.27

This gene — mechanism propensity

0.7033th %ile

GOF

0.6931th %ile

LOF

0.4135th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

LOF71% of P/LP variants are LoF

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

56 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic4

VUS39

Likely Benign8

Benign1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	1	1	0	3
Likely Pathogenic	4	0	0	0	4
VUS	0	39	0	0	39
Likely Benign	0	6	0	2	8
Benign	0	0	1	0	1
Total	5	46	2	2	55

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

31 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap BLOC1S5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →