USP27X

protein-coding

ubiquitin specific peptidase 27 X-linked, the group of Ubiquitin specific peptidases

Gene summary

This gene encodes a member of the peptidase protein family. The encoded protein functions as a deubiquitinase that is involved in upregulation of the pro-apoptotic Bim protein. This protein may act as a tumor suppressor by increasing levels of Bim to counteract anti-apoptotic signals in cancer cells. Mutations in this gene have been associated with X-linked cognitive disability. [provided by RefSeq, Dec 2016]

MANE transcript

NM_001145073.3

Inheritance

ClinVar variants

P:10U:56B:14

Top phenotype

Intellectual developmental disorder, X-linked 105

Max pathogenic AF

—

Genomic locus

chrX:49,879,484-49,882,558

External References & Databases

Ensembl (ENSG00000273820)

Transcript & Mutation Effects

hg38 • Region Span ~3.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual disability, X-linked 105STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010510

Submitter: PanelApp Australia

intellectual disability, X-linked 105STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010510

Submitter: G2P

non-syndromic X-linked intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

X-linked intellectual disabilityLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0100284

Submitter: ClinGen

The *USP27X* gene encodes a deubiquitinase highly expressed in the brain. To date, three variants in *USP27X* have been published in two large exome sequencing studies of families with X-linked intellectual disability. In 2016, Hu et al. (PMID: 25644381) reported a frameshift variant in a multigenerational family with three affected males with borderline to moderate ID, variable absent or poor speech, and behavioral problems. They also reported a missense variant in a family with four affected males, but only one was genotyped. This variant was not scored as there is insufficient evidence to support its pathogenicity. In 2019, Sanchis-Juan et al. (PMID: 31316545) reported a different frameshift variant in two half-siblings with developmental delay and intellectual disability, as well as dysmorphic facial features in one individual. ClinVar contains one record of a likely pathogenic nonsense variant related to a neurodevelopmental disorder (Variation ID: 1321965). In the absence of additional information about the phenotype and the presence of other pathogenic variants, this variant was not scored. Additionally, DECIPHER has a *de novo* missense variant in an individual with global developmental delay and mild intellectual disability who also carries a pathogenic frameshift variant in *SHANK3*, implicated in Phelan-McDermid syndrome (DECIPHER Patient ID: 482675). Therefore, the role of the variant in *USP27X* cannot be determined and was not scored. *USP27X* is constrained for both loss-of-function and missense variants (pLI 0.92 and missense Z score 3.18, gnomAD V2.1.1). No experimental evidence supporting this gene-disease relationship was identified. In summary, there is limited evidence at this time to support the relationship between *USP27X* and X-linked intellectual disability. Additional studies are required to verify this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 1, 2023 (SOP Version 9).

intellectual disability, X-linked 105STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010510

Submitter: Ambry Genetics

intellectual disability, X-linked 105STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010510

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 105XL

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

Refs: 25644381

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to USP27X variants in ClinVar

8 Conditions Cataloged

not providedTotal: 36

Inborn genetic diseasesTotal: 21

Intellectual disability, X-linked 105Total: 20

not specifiedTotal: 5

USP27X-related disorderTotal: 3

Neurodevelopmental disorderTotal: 1

Paediatric disordersTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001145073.3. 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				9 clinvar	2 clinvar	11
missense	1 clinvar	2 clinvar	53 clinvar	2 clinvar	1 clinvar	59
nonsense		2 clinvar	1 clinvar			3
start loss						0
frameshift	2 clinvar	3 clinvar	2 clinvar			7
splice donor/acceptor (+/-2bp)						0
Total	3	7	56	11	3	80

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001145073.3	RefSeq	NP_001138545.1	1	MANE Select
ENST00000621775.2	Ensembl	ENSP00000483631.1	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

ubiquitin-dependent protein catabolic process
protein deubiquitination
positive regulation of apoptotic process
protein stabilization
protein K63-linked deubiquitination

Molecular Function

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

Cellular Component

nucleus
cytosol

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Deubiquitinase that can reduce the levels of BCL2L11/BIM ubiquitination and stabilize BCL2L11 in response to the RAF-MAPK- degradation signal. By acting on BCL2L11 levels, may counteract the anti-apoptotic effects of MAPK activity. {ECO:0000250|UniProtKB:Q8CEG8}.;
Disease: DISEASE: Mental retardation, X-linked 105 (MRX105) [MIM:300984]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. {ECO:0000269|PubMed:25644381}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.110

Essentials

Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

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