GeneBe

OTUD7A

protein-coding

OTU deubiquitinase 7A, the group of OTU domain containing

Gene summary

The protein encoded by this gene is a deubiquitinizing enzyme and possible tumor suppressor. The encoded protein acts on TNF receptor associated factor 6 (TRAF6) to control nuclear factor kappa B expression. However, this gene is downregulated by SNAIL1 in hepatocellular carcinoma cells, contributing to their progression and malignancy. [provided by RefSeq, Aug 2016]

Previous symbols:
  • C15orf16
  • OTUD7

MANE transcript

NM_001382637.1

Inheritance

AR, AD

ClinVar variants

P:3U:158B:16

Top phenotype

Neurodevelopmental disorder with hypotonia and seizures

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr15:31,475,398-31,870,789

External References & Databases

Ensembl (ENSG00000169918)NCBI Gene (161725)OMIM (612024)HGNC:20718GenCCUniProt (Q8TE49)AlphaFoldClinVar (OTUD7A)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~395.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

*OTUD7A* is one of the genes within the recurrent 15q13.3 region. Individuals with heterozygous deletions of this region have phenotypes including intellectual disability, global developmental delays, autism spectrum disorder, and seizures (see the following dosage sensitivity curations for more information: [https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46295](https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46295), [https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37411](https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37411)). Heterozygous sequence variants in *OTUD7A* have been observed in individuals with autism spectrum disorder and schizophrenia (PMIDs: 29395074, 35931052). Because these phenotypes do not include epilepsy, the Epilepsy GCEP is not evaluating the gene-disease relationship for heterozygous OTUD7A sequence variants. Biallelic variants in *OTUD7A* were first reported in a patient with autosomal recessive complex neurodevelopmental disorder (MONDO:0100038) in 2020 (PMID: 31997314). This patient was found to have a homozygous p.Leu233Phe variant, and presented with global developmental delay, epilepsy, and hypotonia (PMID:29395074). The mechanism of pathogenicity is not clear at this time, but it has been suggested that the p.Leu233Phe variant results in loss of function (PMID:31997314). Later, another patient with a frameshift variant and the typical 15q13.3 deletion was reported with intellectual disability, epilepsy, global developmental delays, and dysmorphic features (PMID:33381903). This case has not been awarded points as part of our curation. In summary, there is limited evidence to support the relationship between biallelic variants in *OTUD7A* and autosomal recessive complex neurodevelopmental disorder. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on the meeting date June 6, 2023 (SOP Version 9).

neurodevelopmental disorder with hypotonia and seizuresMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0968979

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with hypotonia and seizuresAD/AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Heterozygotes are described as manifesting with milder neurocognitive sequelae

Refs: 33381903; 31997314Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OTUD7A variants in ClinVar

11 Conditions Cataloged
not specifiedTotal: 146
OTUD7A-related disorderTotal: 20
not providedTotal: 14
Neurodevelopmental disorder with hypotonia and seizuresTotal: 2
Neurodevelopmental disorderTotal: 1
Epileptic encephalopathyTotal: 1
Non-syndromic intellectual disabilityTotal: 1
Language disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001382637.1. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
9
clinvar
5
clinvar
 16
missense
1
clinvar
150
clinvar
1
clinvar
1
clinvar
 153
nonsense
2
clinvar
 2
start loss
0
frameshift
1
clinvar
4
clinvar
 5
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total21158106177

Highest pathogenic variant AF is 0.000006986441

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001382637.1RefSeqNP_001369566.111MANE Select
ENST00000307050.6EnsemblENSP00000305926.511MANE Select
NM_001329907.2RefSeqNP_001316836.18Standard
NM_130901.3RefSeqNP_570971.111Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Post-translational protein modification
  • Metabolism of proteins
  • Ovarian tumor domain proteases
  • Deubiquitination

Biological Process

  • protein deubiquitination
  • protein K11-linked deubiquitination
  • negative regulation of I-kappaB kinase/NF-kappaB signaling
  • protein K63-linked deubiquitination
  • protein K48-linked deubiquitination

Molecular Function

  • DNA binding
  • thiol-dependent ubiquitin-specific protease activity
  • zinc ion binding
  • thiol-dependent ubiquitinyl hydrolase activity
  • K63-linked polyubiquitin modification-dependent protein binding

Cellular Component

  • nucleus
  • cytoplasm
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000307050
Coding exons
11
Length
387664
Individuals with no LoFs
125721
Homozygous LoFs
0
Heterozygous LoFs
25
Defined
125746
p
0.0000994
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.872844560.6230.00003055862
Missense (PolyPhen)125272.190.459243118
Synonymous-0.5722242131.050.00001651949
Loss of Function4.39531.60.1580.00000152396

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian0.00100.0010notable
Finnish0.000140.000092rare
European (Non-Finnish)0.0000190.000018rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Has deubiquitinating activity towards 'Lys-11'-linked polyubiquitin chains. {ECO:0000269|PubMed:20622874, ECO:0000269|PubMed:23827681}.;

Recessive Scores

pRec
0.116

Intolerance Scores

LoFtool
0.0796
RVIS EVS
-1.15
RVIS percentile EVS
6.23

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.102

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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