OTUB1

Chr 11

OTU deubiquitinase, ubiquitin aldehyde binding 1

Also known as: HSPC263, OTB1, OTU1

NCBI Gene: 55611 ENSG00000167770 UniProt: Q96FW1

The protein functions as a highly specific ubiquitin protease that removes Lys-48-linked ubiquitin chains from proteins, thereby preventing their degradation and regulating protein turnover, T-cell immune responses, and estrogen receptor signaling. Mutations cause autosomal dominant intellectual disability with distinctive facial features and developmental delay. This gene is highly constrained against loss-of-function mutations, indicating that proper protein function is critical for normal development.

ResearchSummary from RefSeq, UniProt

The product of this gene is a member of the OTU (ovarian tumor) superfamily of predicted cysteine proteases. The encoded protein is a highly specific ubiquitin iso-peptidase, and cleaves ubiquitin from branched poly-ubiquitin chains but not from ubiquitinated substrates. It interacts with another ubiquitin protease and an E3 ubiquitin ligase that inhibits cytokine gene transcription in the immune system. It is proposed to function in specific ubiquitin-dependent pathways, possibly by providing an editing function for polyubiquitin chain growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.31

LOEUF· LoF intol.

—

Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.971

Z-score 3.39

OE 0.07 (0.02–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.20Z-score

OE missense 0.52 (0.43–0.62)

85 obs / 164.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.07 (0.02–0.31)

0≤0.351.4

Missense OE?0.52 (0.43–0.62)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 1 / 15.4Missense obs/exp: 85 / 164.1Syn Z: -0.38

Background carrier burden — how many people carry a rare variant somewhere in OTUB1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 190

345 rare PASS variants

Rare truncating (LoF)

1 in 3,600

39 rare PASS variants

Rare synonymous (reference)

1 in 220

208 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for OTUB1. 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 250	1 in 3,700
South Asian	~43k	1 in 230	1 in 2,700
Remaining (unassigned)	~30k	1 in 130	1 in 1,900
European (Finnish)	~27k	1 in 550	≈ 1 in 25,000
Admixed American	~22k	1 in 190	1 in 4,100
African / African American	~21k	1 in 280	1 in 2,000
East Asian	~20k	1 in 390	≈ 1 in 8,000
Ashkenazi Jewish	~13k	1 in 960	none seen
Middle Eastern	~2,884	1 in 150	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): All 7 coding exons well covered in gnomAD exomes and genomes.? see exons ↓