BORCS5

Chr 12

BLOC-1 related complex subunit 5

Also known as: LOH12CR1, LOH1CR12

NCBI Gene: 118426 ENSG00000165714 UniProt: Q969J3

The BORCS5 protein is part of the BORC complex that regulates lysosome movement and localization by recruiting motor proteins to transport lysosomes along microtubules to the cell periphery. Mutations in BORCS5 cause autosomal recessive neurodegeneration with brain iron accumulation, typically presenting in childhood with progressive movement disorders and cognitive decline. The gene shows relatively low constraint to loss-of-function variation (pLI 0.001, LOEUF 1.13).

ResearchSummary from RefSeq, UniProt

Involved in lysosome localization and organelle transport along microtubule. Located in cytoplasmic side of lysosomal membrane; plasma membrane; and plus-end kinesin complex. Part of BORC complex. Implicated in colorectal adenocarcinoma. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.13

Clinical Summary— BORCS5

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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

1 unique Pathogenic / Likely Pathogenic· 26 VUS of 37 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.13LOEUF

pLI 0.001

Z-score 1.29

OE 0.57 (0.31–1.13)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.26Z-score

OE missense 0.93 (0.80–1.09)

113 obs / 121.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.31–1.13)

0≤0.351.4

Missense OE?0.93 (0.80–1.09)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 6 / 10.5Missense obs/exp: 113 / 121.0Syn Z: -1.16

This gene — mechanism propensity

0.7327th %ile

GOF

0.6442th %ile

LOF

0.3647th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-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

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.

ClinVar Variant Classifications

37 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS26

Likely Benign1

Conflicting1

Likely Pathogenic

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	1	0	0	0	1
VUS	0	26	0	0	26
Likely Benign	0	1	0	0	1
Benign	0	0	0	0	0
Conflicting	—				1
Total	1	27	0	0	29

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

View in ClinVar →

45 pathogenic / likely-pathogenic (of 54) ClinVar copy-number / structural variants overlap BORCS5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →