VPS51

Chr 11

VPS51 subunit of GARP complex

Also known as: ANG2, ANG3, C11orf2, C11orf3, FFR, PCH13

NCBI Gene: 738 ENSG00000149823 UniProt: Q9UID3

The protein functions as a component of the GARP complex, facilitating retrograde transport from endosomes to the trans-Golgi network and maintaining protein retrieval, lysosome function, and autophagy. Biallelic mutations cause pontocerebellar hypoplasia type 13, an autosomal recessive neurodevelopmental disorder affecting the brainstem and cerebellum. The gene shows relatively low constraint to loss-of-function variation with a LOEUF score of 0.924.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the vacuolar protein sorting-associated protein 51 family. The encoded protein is a component of the Golgi-associated retrograde protein complex which acts as a tethering factor for carriers in retrograde transport from the early and late endosomes to the trans-Golgi network. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtPontocerebellar hypoplasia 13

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.92

LOEUF

Mechanism· predicted

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?

0.92LOEUF

pLI 0.000

Z-score 1.87

OE 0.62 (0.42–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.66Z-score

OE missense 0.67 (0.61–0.73)

347 obs / 517.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.62 (0.42–0.92)

0≤0.351.4

Missense OE?0.67 (0.61–0.73)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 17 / 27.6Missense obs/exp: 347 / 517.5Syn Z: 1.79

Background carrier burden — how many people carry a rare variant somewhere in VPS51?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 62

1,148 rare PASS variants

Rare truncating (LoF)

1 in 210

186 rare PASS variants

Rare synonymous (reference)

1 in 80

548 rare PASS variants

Rare missense and truncating variants are carried at similar rates in VPS51; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 78	1 in 350
South Asian	~43k	1 in 57	1 in 1,100
Remaining (unassigned)	~30k	1 in 63	1 in 520
European (Finnish)	~27k	1 in 130	1 in 520
Admixed American	~22k	1 in 57	1 in 710
African / African American	~21k	1 in 51	1 in 680
East Asian	~20k	1 in 54	1 in 710
Ashkenazi Jewish	~13k	1 in 260	1 in 510
Middle Eastern	~2,884	1 in 93	1 in 520

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 9 of 10 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 10.? see exons ↓