OTUD5

protein-coding

OTU deubiquitinase 5, the group of OTU domain containing

Gene summary

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]

MANE transcript

NM_001136157.2

Inheritance

ClinVar variants

P:10U:113B:13

Top phenotype

Multiple congenital anomalies-neurodevelopmental syndrome, X-linked

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:48,922,024-48,958,386

External References & Databases

Ensembl (ENSG00000068308)

Transcript & Mutation Effects

hg38 • Region Span ~36.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

multiple congenital anomalies/dysmorphic syndromeMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0019042

Submitter: Ambry Genetics

multiple congenital anomalies-neurodevelopmental syndrome, X-linkedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0025351

Submitter: Labcorp Genetics (formerly Invitae)

multiple congenital anomalies-neurodevelopmental syndrome, X-linkedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0025351

Submitter: PanelApp Australia

multiple congenital anomalies-neurodevelopmental syndrome, X-linkedMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0025351

Submitter: ClinGen

The *OTUD5* gene is located on chromosome X at Xp11.23 and encodes a lysine-48/lysine-63 linkage-specific deubiquitinase. *OTUD5* was first reported in relation to X-linked multiple congenital anomalies-neurodevelopmental syndrome in 2021 (Tripolszki et al.,PMID: 33131077). This disorder is characterized by characteristic craniofacial features, intellectual disability and global developmental delays, poor growth and with some individuals presenting with cardiac, skeletal, and genitourinary anomalies. The disorder has a very variable presentation. At least 11 unique variants (10 missense, 1 inframe deletion) have been reported in 12 probands in five publications (PMIDs: 33523931, 33131077, 35143101, 38037881, 33748114) and are included in this curation. This gene-disease relationship is supported by biochemical function studies, protein-protein interactions, and functional alterations in patient derived cells (PMIDs: 23827681, 28343629, 33523931). The mechanism of pathogenicity appears to be hypomorphic variants that are predominantly missense. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date July 19, 2024 (SOP Version 10).

multiple congenital anomalies-neurodevelopmental syndrome, X-linkedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0025351

Submitter: G2P

Clinical Genomic Database (CGD)

Multiple congenital anomalies-neurodevelopmental syndrome, X-linkedXL

Manifestation: Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Renal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 33131077; 33523931

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OTUD5 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 38

Inborn genetic diseasesTotal: 37

Multiple congenital anomalies-neurodevelopmental syndrome, X-linkedTotal: 19

OTUD5-related disorderTotal: 7

not specifiedTotal: 4

Dysplastic corpus callosumTotal: 1

Neurodegeneration with brain iron accumulation 5Total: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001136157.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	9 clinvar	1 clinvar	17
missense	4 clinvar	5 clinvar	84 clinvar	3 clinvar		96
nonsense	1 clinvar		3 clinvar			4
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			18 clinvar			18
Total	5	5	113	12	1	136

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 51 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001136157.2	RefSeq	NP_001129629.1	9	MANE Select
ENST00000376488.8	Ensembl	ENSP00000365671.3	9	MANE Select
NM_001136158.2	RefSeq	NP_001129630.1	9	Standard
NM_001136159.2	RefSeq	NP_001129631.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
otud5b	Danio rerio	Structure: trunk Quality: bent abnormal

Gene / Model

Organism

Observed Phenotype

otud5b

Danio rerio

Structure: trunk

Quality: bent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RIG-I-like receptor signaling pathway - Homo sapiens (human)
Regulation of toll-like receptor signaling pathway
Gastric Cancer Network 2
RIG-I-like Receptor Signaling
Post-translational protein modification

Biological Process

protein deubiquitination
negative regulation of type I interferon production
response to lipopolysaccharide
protein K63-linked deubiquitination
protein K48-linked deubiquitination

Molecular Function

thiol-dependent ubiquitin-specific protease activity
Lys63-specific deubiquitinase activity
ubiquitinyl hydrolase activity
Lys48-specific deubiquitinase activity

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000156084
Coding exons: 9
Length: 36344
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.99	44	205	0.215	0.0000164	3643
Missense (PolyPhen)		3	60.517	0.049573		961
Synonymous	0.0542	79	79.6	0.992	0.00000624	1188
Loss of Function	3.85	0	17.2	0.00	0.00000132	262

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Deubiquitinating enzyme that functions as negative regulator of the innate immune system. Acts via TRAF3 deubiquitination and subsequent suppression of type I interferon (IFN) production. Has peptidase activity towards 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. Can also cleave 'Lys-11'- linked ubiquitin chains (in vitro). {ECO:0000269|PubMed:17991829, ECO:0000269|PubMed:22245969, ECO:0000269|PubMed:23827681}.;

Recessive Scores

pRec: 0.105

Intolerance Scores

RVIS EVS: -0.16
RVIS percentile EVS: 41.25

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.772

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium