OTUD6B

protein-coding

OTU deubiquitinase 6B, the group of OTU domain containing

Gene summary

This gene encodes a member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes. Deubiquitinating enzymes are primarily involved in removing ubiquitin from proteins targeted for degradation. This protein may function as a negative regulator of the cell cycle in B cells. [provided by RefSeq, Nov 2013]

MANE transcript

NM_016023.5

Inheritance

ClinVar variants

P:21U:60B:9

Top phenotype

Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies (IDDFSDA)

gnomAD constraint

pLI —, LoF o/e 0.82

Max pathogenic AF

—

Genomic locus

chr8:91,070,196-91,087,095

External References & Databases

Ensembl (ENSG00000155100)

Transcript & Mutation Effects

hg38 • Region Span ~16.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000508

Submitter: ClinGen

*OTUD6B* was first reported in relation to autosomal recessive syndromic intellectual disability in 2017; this condition is also referred to as intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies (Santiago-Sim et al., PMID: 28343629). Individuals with variants in *OTUD6B* have been reported to present with intellectual disability, speech delay, seizures, microcephaly, gross motor delay, intrauterine growth restriction, feeding difficulties, facial dysmorphism, and various, nonspecific abnormalities of the fingers/toes. This curation includes seven predicted null variants (nonsense, frameshift, splice) from 6 probands in 4 publications (PMIDs: 28343629, 34354232, 32181568, 30364145). Additional evidence (including individuals with putative loss of function and missense variants) has been reported in the literature (PMIDs: 30364145, 35707595, 35707595, 35430327, 32924626, 31147255), but these cases were not scored as the maximum for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. Segregation of variants with disease in multiple families also supports this gene-disease relationship (PMIDs: 28343629, 34354232). This gene-disease relationship is also supported by experimental evidence including an animal model and functional alteration studies using patient cells (PMID: 28343629). In summary, there is definitive evidence supporting the relationship between *OTUD6B* and autosomal recessive syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen ID Autism GCEP on the meeting date 08/22/2024 (SOP Version 10).

intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomaliesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044319

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomaliesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044319

Submitter: PanelApp Australia

intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomaliesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044319

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies (IDDFSDA)AR

Manifestation: Craniofacial; Musculoskeletal; 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

Refs: 28343629

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OTUD6B variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 42

Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomaliesTotal: 29

not providedTotal: 28

OTUD6B-related disorderTotal: 7

Intellectual disabilityTotal: 5

Dysmorphic featuresTotal: 4

EpilepsyTotal: 4

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016023.5. 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			1 clinvar	6 clinvar		7
missense		5 clinvar	50 clinvar	3 clinvar		58
nonsense	4 clinvar	2 clinvar	3 clinvar			9
start loss						0
frameshift	5 clinvar	2 clinvar	1 clinvar			8
splice donor/acceptor (+/-2bp)	3 clinvar		5 clinvar			8
Total	12	9	60	9	0	90

Highest pathogenic variant AF is 0.000115809424

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016023.5	RefSeq	NP_057107.4	7	MANE Select
ENST00000404789.8	Ensembl	ENSP00000384190.4	7	MANE Select
NM_001286745.3	RefSeq	NP_001273674.1	5	Standard
NM_001416022.1	RefSeq	NP_001402951.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

EGFR1

Biological Process

cell population proliferation
protein deubiquitination
proteasome assembly

Molecular Function

thiol-dependent ubiquitin-specific protease activity
thiol-dependent ubiquitinyl hydrolase activity

Cellular Component

eukaryotic translation initiation factor 4F complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000285420
Coding exons: 7
Length: 16900
Individuals with no LoFs: 125523
Homozygous LoFs: 0
Heterozygous LoFs: 70
Defined: 125593
p: 0.000279

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.296	145	155	0.933	0.00000738	2084
Missense (PolyPhen)		53	61.541	0.86121		858
Synonymous	-0.0496	55	54.5	1.01	0.00000257	576
Loss of Function	0.650	12	14.7	0.817	6.91e-7	218

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00020	0.00012	rare
Latino/Admixed American	0.0010	0.00087	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00055	0.00054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00016	0.00015	rare
South Asian	0.00014	0.00013	rare
Other	0.00077	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Isoform 1: Deubiquitinating enzyme that may play a role in the ubiquitin-dependent regulation of protein synthesis, downstream of mTORC1 (PubMed:21267069, PubMed:27864334). May associate with the protein synthesis initiation complex and modify its ubiquitination to repress translation (PubMed:27864334). May also repress DNA synthesis and modify different cellular targets thereby regulating cell growth and proliferation (PubMed:27864334). May also play a role in proteasome assembly and function (PubMed:28343629). {ECO:0000269|PubMed:21267069, ECO:0000269|PubMed:27864334, ECO:0000269|PubMed:28343629}.;
Disease: DISEASE: Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies (IDDFSDA) [MIM:617452]: An autosomal recessive severe multisystem disorder characterized by poor overall growth, developmental delay, early- onset seizures, intellectual disability, and dysmorphic features. Additional features include microcephaly, absent speech, hypotonia, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. {ECO:0000269|PubMed:28343629}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0953

Intolerance Scores

LoFtool: 0.587
RVIS EVS: 0.71
RVIS percentile EVS: 85.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.574

Gene Damage Prediction

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