EXOSC9

Chr 4AR

exosome component 9

Also known as: PCH1D, PM/Scl-75, PMSCL1, RRP45, Rrp45p, p5, p6

NCBI Gene: 5393 ENSG00000123737 UniProt: Q06265 OMIM: 606180

This gene encodes a non-catalytic component of the RNA exosome complex, which degrades and processes RNA in both the nucleus and cytoplasm, including mRNA turnover, ribosomal RNA maturation, and elimination of aberrant transcripts. Mutations cause pontocerebellar hypoplasia type 1D, a severe early-onset neurodevelopmental disorder affecting the brainstem and cerebellum, inherited in an autosomal recessive pattern. The gene is extremely intolerant to loss-of-function variants, indicating that proper RNA processing is essential for normal cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a component of the human exosome, a exoribonuclease complex which processes and degrades RNA in the nucleus and cytoplasm. This component may play a role in mRNA degradation and the polymyositis/scleroderma autoantigen complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Pontocerebellar hypoplasia, type 1DMIM #618065

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Pontocerebellar hypoplasia, type 1D; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.11

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.11LOEUF

pLI 0.000

Z-score 1.12

OE 0.76 (0.54–1.11)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.15Z-score

OE missense 0.97 (0.87–1.08)

234 obs / 240.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.76 (0.54–1.11)

0≤0.351.4

Missense OE?0.97 (0.87–1.08)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 20 / 26.2Missense obs/exp: 234 / 240.7Syn Z: 0.17

Background carrier burden — how many people carry a rare variant somewhere in EXOSC9?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

628 rare PASS variants

Rare truncating (LoF)

1 in 690

150 rare PASS variants

Rare synonymous (reference)

1 in 260

192 rare PASS variants

Rare missense and truncating variants are carried at similar rates in EXOSC9; 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 190	1 in 700
South Asian	~43k	1 in 72	1 in 520
Remaining (unassigned)	~30k	1 in 110	1 in 850
European (Finnish)	~27k	1 in 890	1 in 2,200
Admixed American	~22k	1 in 110	1 in 920
African / African American	~21k	1 in 100	1 in 450
East Asian	~20k	1 in 99	1 in 640
Ashkenazi Jewish	~13k	1 in 370	1 in 1,100
Middle Eastern	~2,884	1 in 180	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): 9 of 12 coding exons well covered in gnomAD exomes; exons 8, 11, 12 marginal. Genomes: all 12.? see exons ↓