OTUD5

Chr XXLR

OTU deubiquitinase 5

Also known as: DUBA, MCAND

NCBI Gene: 55593 ENSG00000068308 UniProt: Q96G74 OMIM: 300713

The protein functions as a deubiquitinase that suppresses type I interferon-dependent innate immune responses by cleaving polyubiquitin chains from essential interferon adaptor proteins, disrupting downstream signaling cascades. Loss-of-function mutations cause X-linked recessive multiple congenital anomalies-neurodevelopmental syndrome. The mechanism involves haploinsufficiency leading to dysregulated innate immune signaling and abnormal neurodevelopment.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the OTU (ovarian tumor) domain-containing cysteine protease superfamily. The OTU domain confers deubiquitinase activity and the encoded protein has been shown to suppress the type I interferon-dependent innate immune response by cleaving the polyubiquitin chain from an essential type I interferon adaptor protein. Cleavage results in disassociation of the adaptor protein from a downstream signaling complex and disruption of the type I interferon signaling cascade. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Oct 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Multiple congenital anomalies-neurodevelopmental syndrome, X-linkedMIM #301056

XLR

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · multiple congenital anomalies-neurodevelopmental syndrome, X-linked · XL · ClinGen 2024

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.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.17

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.17LOEUF

pLI 0.997

Z-score 3.85

OE 0.00 (0.00–0.17)

Highly constrained

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

Missense Constraint?

3.99Z-score

OE missense 0.21 (0.17–0.28)

44 obs / 204.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.17)

0≤0.351.4

Missense OE?0.21 (0.17–0.28)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 0 / 17.2Missense obs/exp: 44 / 204.9Syn Z: 0.05

Background carrier burden — how many people carry a rare variant somewhere in OTUD5?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 310

259 rare PASS variants

Rare truncating (LoF)

1 in 36,000

15 rare PASS variants

Rare synonymous (reference)

1 in 340

248 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for OTUD5. 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)	~561k	1 in 610	1 in 49,000
South Asian	~36k	1 in 640	≈ 1 in 8,700
Remaining (unassigned)	~31k	1 in 220	≈ 1 in 15,000
European (Finnish)	~27k	1 in 1,200	≈ 1 in 8,800
Admixed American	~23k	1 in 570	≈ 1 in 5,200
African / African American	~21k	1 in 560	none seen
East Asian	~20k	1 in 580	none seen
Ashkenazi Jewish	~13k	1 in 850	none seen
Middle Eastern	~2,758	≈ 1 in 1,800	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.