OTUD5

Chr X

OTU deubiquitinase 5

Also known as: DUBA, MCAND

NCBI Gene: 55593 ENSG00000068308 UniProt: Q96G74

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.

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.17

Clinical Summary— OTUD5

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Gene-Disease Validity (ClinGen)

multiple congenital anomalies-neurodevelopmental syndrome, X-linked · XLModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

10 unique Pathogenic / Likely Pathogenic· 69 VUS of 151 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongOTUD5-related neurodevelopmental disorderOTHERXLR

This gene — mechanism propensity

0.18100th %ile

GOF

0.4184th %ile

LOF

0.85top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 20% of P/LP variants are LoF · LOEUF 0.17

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

151 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic5

VUS69

Likely Benign11

Benign1

Conflicting4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	4	0	0	5
Likely Pathogenic	1	4	0	0	5
VUS	1	66	2	0	69
Likely Benign	0	2	0	9	11
Benign	0	0	0	1	1
Conflicting	—				4
Total	3	76	2	10	95

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

62 pathogenic / likely-pathogenic (of 70) ClinVar copy-number / structural variants overlap OTUD5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →