VPS45

Chr 1AR

vacuolar protein sorting 45 homolog

Also known as: H1, H1VPS45, SCN5, VPS45A, VPS45B, VPS54A, VSP45, VSP45A

NCBI Gene: 11311 ENSG00000136631 UniProt: Q9NRW7 OMIM: 610035

Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene is a member of the Sec1 domain family, and shows a high degree of sequence similarity to mouse, rat and yeast Vps45. The exact function of this gene is not known, but its high expression in peripheral blood mononuclear cells suggests a role in trafficking proteins, including inflammatory mediators. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2013]

OMIM Research

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neutropenia, severe congenital, 5, autosomal recessiveMIM #615285

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Neutropenia, severe congenital, 5, autosomal recessive; no ClinGen or GenCC tier

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.66

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.66LOEUF

pLI 0.000

Z-score 3.14

OE 0.43 (0.28–0.66)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.63Z-score

OE missense 0.74 (0.66–0.83)

229 obs / 309.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.28–0.66)

0≤0.351.4

Missense OE?0.74 (0.66–0.83)

0≤0.61.4

Synonymous OE?0.79

0≤1.21.6

LoF obs/exp: 15 / 35.1Missense obs/exp: 229 / 309.5Syn Z: 1.67

Background carrier burden — how many people carry a rare variant somewhere in VPS45?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 88

724 rare PASS variants

Rare truncating (LoF)

1 in 940

106 rare PASS variants

Rare synonymous (reference)

1 in 260

251 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for VPS45. 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 100	1 in 980
South Asian	~43k	1 in 82	1 in 340
Remaining (unassigned)	~30k	1 in 82	1 in 1,100
European (Finnish)	~27k	1 in 280	≈ 1 in 8,900
Admixed American	~22k	1 in 76	1 in 1,200
African / African American	~21k	1 in 81	1 in 670
East Asian	~20k	1 in 100	1 in 780
Ashkenazi Jewish	~13k	1 in 260	1 in 980
Middle Eastern	~2,884	1 in 110	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 15 coding exons well covered in gnomAD exomes; exon 3 marginal. Genomes: 14 of 15 (exon 4 below).? see exons ↓