GeneBe

STUB1

protein-coding

STIP1 homology and U-box containing protein 1, the group of U-box domain containing|Tetratricopeptide repeat domain containing

Gene summary

This gene encodes a protein containing tetratricopeptide repeat and a U-box that functions as a ubiquitin ligase/cochaperone. The encoded protein binds to and ubiquitinates shock cognate 71 kDa protein (Hspa8) and DNA polymerase beta (Polb), among other targets. Mutations in this gene cause spinocerebellar ataxia, autosomal recessive 16. Alternative splicing results in multiple transcript variants. There is a pseudogene for this gene on chromosome 2. [provided by RefSeq, Jun 2014]

MANE transcript

NM_005861.4

Inheritance

AD, AR, Digenic

ClinVar variants

P:57U:140B:50

Top phenotype

Spinocerebellar ataxia 48; Spinocerebellar ataxia, autosomal recessive 16

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr16:680,224-682,870

External References & Databases

Ensembl (ENSG00000103266)NCBI Gene (10273)OMIM (607207)HGNC:11427GenCCUniProt (Q9UNE7)AlphaFoldClinVar (STUB1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~2.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia 48STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032526

Submitter: Ambry Genetics

autosomal recessive spinocerebellar ataxia 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014339

Submitter: Ambry Genetics

spinocerebellar ataxia 48STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032526

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive spinocerebellar ataxia 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014339

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia 48STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032526

Submitter: PanelApp Australia

autosomal recessive spinocerebellar ataxia 16SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014339

Submitter: Orphanet

autosomal recessive spinocerebellar ataxia 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014339

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 48; Spinocerebellar ataxia, autosomal recessive 16AD/AR/Digenic

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: Hypogonadism has been described in some individuals with Spinocerebellar ataxia, autosomal recessive 16

Refs: 24312598; 24113144; 24719489; 24742043; 25258038; 30381368; 34906452Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to STUB1 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 188
Spinocerebellar ataxia 48Total: 47
Autosomal recessive spinocerebellar ataxia 16Total: 45
not specifiedTotal: 31
Inborn genetic diseasesTotal: 27
STUB1-related disorderTotal: 18
Autosomal dominant and autosomal recessive STUB1-related disordersTotal: 2
Cerebellar ataxiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005861.4. 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
3
clinvar
45
clinvar
 48
missense
9
clinvar
16
clinvar
124
clinvar
5
clinvar
 154
nonsense
1
clinvar
8
clinvar
3
clinvar
 12
start loss
1
clinvar
 1
frameshift
4
clinvar
13
clinvar
1
clinvar
 18
splice donor/acceptor (+/-2bp)
5
clinvar
9
clinvar
 14
Total1443140500247

Highest pathogenic variant AF is 0.0005382712

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005861.4RefSeqNP_005852.27MANE Select
ENST00000219548.9EnsemblENSP00000219548.47MANE Select
NM_001293197.2RefSeqNP_001280126.16Standard
ENST00000564316.1EnsemblENSP00000457090.15Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Ubiquitin mediated proteolysis - Homo sapiens (human)
  • Protein processing in endoplasmic reticulum - Homo sapiens (human)
  • Androgen receptor signaling pathway
  • Parkin-Ubiquitin Proteasomal System pathway
  • Transcriptional regulation by RUNX2

Biological Process

  • protein polyubiquitination
  • response to ischemia
  • DNA repair
  • ubiquitin-dependent protein catabolic process
  • protein quality control for misfolded or incompletely synthesized proteins

Molecular Function

  • G protein-coupled receptor binding
  • ubiquitin-protein transferase activity
  • protein binding
  • enzyme binding
  • kinase binding

Cellular Component

  • ubiquitin ligase complex
  • nucleus
  • nucleoplasm
  • cytoplasm
  • endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000219548
Coding exons
7
Length
2647
Individuals with no LoFs
125645
Homozygous LoFs
0
Heterozygous LoFs
13
Defined
125658
p
0.0000517
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.161431880.7610.00001181977
Missense (PolyPhen)2770.2970.38409712
Synonymous-2.7911179.41.400.00000537552
Loss of Function2.54617.40.3440.00000102180

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.0000450.000044rare
South Asian0.000100.000098rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: E3 ubiquitin-protein ligase which targets misfolded chaperone substrates towards proteasomal degradation. Collaborates with ATXN3 in the degradation of misfolded chaperone substrates: ATXN3 restricting the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. Ubiquitinates NOS1 in concert with Hsp70 and Hsp40. Modulates the activity of several chaperone complexes, including Hsp70, Hsc70 and Hsp90. Mediates transfer of non-canonical short ubiquitin chains to HSPA8 that have no effect on HSPA8 degradation. Mediates polyubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair: catalyzes polyubiquitination by amplifying the HUWE1/ARF- BP1-dependent monoubiquitination and leading to POLB-degradation by the proteasome. Mediates polyubiquitination of CYP3A4. Ubiquitinates EPHA2 and may regulate the receptor stability and activity through proteasomal degradation. Acts as a co-chaperone for HSPA1A and HSPA1B chaperone proteins and promotes ubiquitin- mediated protein degradation (PubMed:27708256). Negatively regulates the suppressive function of regulatory T-cells (Treg) during inflammation by mediating the ubiquitination and degradation of FOXP3 in a HSPA1A/B-dependent manner (PubMed:23973223). Likely mediates polyubiquitination and downregulates plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity. Negatively regulates TGF-beta signaling by modulating the basal level of SMAD3 via ubiquitin-mediated degradation (PubMed:24613385). May regulate myosin assembly in striated muscles together with UBE4B and VCP/p97 by targeting myosin chaperone UNC45B for proteasomal degradation (PubMed:17369820). Mediates ubiquitination of RIPK3 leading to its subsequent proteasome-dependent degradation (PubMed:29883609). {ECO:0000269|PubMed:10330192, ECO:0000269|PubMed:11146632, ECO:0000269|PubMed:11557750, ECO:0000269|PubMed:15466472, ECO:0000269|PubMed:17369820, ECO:0000269|PubMed:19103148, ECO:0000269|PubMed:19567782, ECO:0000269|PubMed:19713937, ECO:0000269|PubMed:23973223, ECO:0000269|PubMed:23990462, ECO:0000269|PubMed:24613385, ECO:0000269|PubMed:28813410, ECO:0000269|PubMed:29883609}.;
Disease
DISEASE: Spinocerebellar ataxia, autosomal recessive, 16 (SCAR16) [MIM:615768]: Spinocerebellar ataxia defines a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR16 is characterized by truncal and limb ataxia resulting in gait instability. Additionally, patients may show dysarthria, nystagmus, spasticity of the lower limbs, and mild peripheral sensory neuropathy. {ECO:0000269|PubMed:24113144, ECO:0000269|PubMed:24312598, ECO:0000269|PubMed:24719489, ECO:0000269|PubMed:24742043, ECO:0000269|PubMed:25258038}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.479

Intolerance Scores

LoFtool
0.503
RVIS EVS
-0.27
RVIS percentile EVS
34.32

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.975

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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