EXOSC8

Chr 13

exosome component 8

Also known as: CIP3, EAP2, OIP2, PCH1C, RRP43, Rrp43p, bA421P11.3, p9

NCBI Gene: 11340 ENSG00000120699 UniProt: Q96B26

The protein is a non-catalytic component of the RNA exosome complex that processes and degrades various RNA species in both the nucleus and cytoplasm, including mRNAs containing AU-rich elements. Mutations cause pontocerebellar hypoplasia type 1C, a severe early-onset neurodevelopmental disorder primarily affecting the brainstem and cerebellum, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variation (pLI nearly 1), indicating that heterozygous loss-of-function variants are likely benign in the general population.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a 3'-5' exoribonuclease that specifically interacts with mRNAs containing AU-rich elements. The encoded protein is part of the exosome complex that is important for the degradation of numerous RNA species. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Mar 2009]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtPontocerebellar hypoplasia 1C

Clinical highlights

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

1.69

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — EXOSC8

Authoritative clinical overview · Recommended first read

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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?

1.69LOEUF

pLI 0.000

Z-score -0.66

OE 1.17 (0.82–1.69)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.85Z-score

OE missense 0.80 (0.69–0.94)

115 obs / 143.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.17 (0.82–1.69)

0≤0.351.4

Missense OE?0.80 (0.69–0.94)

0≤0.61.4

Synonymous OE?0.68

0≤1.21.6

LoF obs/exp: 20 / 17.1Missense obs/exp: 115 / 143.5Syn Z: 1.81

Background carrier burden — how many people carry a rare variant somewhere in EXOSC8?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 220

341 rare PASS variants

Rare truncating (LoF)

1 in 300

107 rare PASS variants

Rare synonymous (reference)

1 in 870

99 rare PASS variants

Rare missense and truncating variants are carried at similar rates in EXOSC8; 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 400	1 in 390
South Asian	~43k	1 in 100	1 in 530
Remaining (unassigned)	~30k	1 in 190	1 in 500
European (Finnish)	~27k	1 in 760	≈ 1 in 27,000
Admixed American	~22k	1 in 140	1 in 1,700
African / African American	~21k	1 in 120	1 in 660
East Asian	~20k	1 in 330	1 in 1,700
Ashkenazi Jewish	~13k	1 in 370	none seen
Middle Eastern	~2,884	1 in 280	≈ 1 in 960

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): 1 of 11 coding exons well covered in gnomAD exomes; exons 2, 3, 4, 5, 6 and 5 more marginal. Genomes: all 11.? see exons ↓