CHMP5

Chr 9

charged multivesicular body protein 5

Also known as: C9orf83, CGI-34, HSPC177, PNAS-2, SNF7DC2, Spike, Vps60

NCBI Gene: 51510 ENSG00000086065 UniProt: Q9NZZ3 OMIM: 610900

The CHMP5 protein is a component of the ESCRT-III complex that mediates endosomal cargo sorting into multivesicular bodies and membrane fission events including cytokinesis. Currently, no Mendelian diseases have been definitively associated with CHMP5 mutations in OMIM or major clinical databases. The gene shows low constraint against loss-of-function variants (pLI = 0.007, LOEUF = 0.81), suggesting that heterozygous loss-of-function mutations may be tolerated.

OMIM ResearchSummary from RefSeq, UniProt

CHMP5 belongs to the chromatin-modifying protein/charged multivesicular body protein (CHMP) family. These proteins are components of ESCRT-III (endosomal sorting complex required for transport III), a complex involved in degradation of surface receptor proteins and formation of endocytic multivesicular bodies (MVBs). Some CHMPs have both nuclear and cytoplasmic/vesicular distributions, and one such CHMP, CHMP1A (MIM 164010), is required for both MVB formation and regulation of cell cycle progression (Tsang et al., 2006 [PubMed 16730941]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.81

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.007

Z-score 2.10

OE 0.41 (0.22–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.73Z-score

OE missense 0.81 (0.68–0.96)

95 obs / 117.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.41 (0.22–0.81)

0≤0.351.4

Missense OE?0.81 (0.68–0.96)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 6 / 14.7Missense obs/exp: 95 / 117.4Syn Z: -0.47

Background carrier burden — how many people carry a rare variant somewhere in CHMP5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 560

232 rare PASS variants

Rare truncating (LoF)

1 in 10,000

30 rare PASS variants

Rare synonymous (reference)

1 in 1,200

82 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CHMP5. 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 630	1 in 23,000
South Asian	~43k	1 in 340	≈ 1 in 11,000
Remaining (unassigned)	~30k	1 in 310	≈ 1 in 15,000
European (Finnish)	~27k	1 in 1,300	≈ 1 in 13,000
Admixed American	~22k	1 in 430	≈ 1 in 7,500
African / African American	~21k	1 in 370	≈ 1 in 6,400
East Asian	~20k	1 in 280	1 in 1,400
Ashkenazi Jewish	~13k	1 in 770	none seen
Middle Eastern	~2,884	≈ 1 in 690	≈ 1 in 1,400

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): 6 of 8 coding exons well covered in gnomAD exomes; exons 3, 6 marginal. Genomes: all 8.? see exons ↓