STUB1

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

Basic information

Region (hg38): 16:680223-682870

Links

ENSG00000103266 ∙ NCBI:10273 ∙ OMIM:607207 ∙ HGNC:11427 ∙ Uniprot:Q9UNE7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal recessive spinocerebellar ataxia 16 (Supportive), mode of inheritance: AR
• autosomal recessive spinocerebellar ataxia 16 (Strong), mode of inheritance: AR
• spinocerebellar ataxia 48 (Strong), mode of inheritance: AD
• spinocerebellar ataxia 48 (Strong), mode of inheritance: AD
• autosomal recessive spinocerebellar ataxia 16 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spinocerebellar ataxia 48; Spinocerebellar ataxia, autosomal recessive 16	AD/AR/Digenic	General	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	Neurologic	24312598; 24113144; 24719489; 24742043; 25258038; 30381368; 34906452
Hypogonadism has been described in some individuals with Spinocerebellar ataxia, autosomal recessive 16

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the STUB1 gene.

• not provided (97 variants)
• Spinocerebellar ataxia 48 (22 variants)
• Autosomal recessive spinocerebellar ataxia 16 (21 variants)
• Inborn genetic diseases (5 variants)
• not specified (4 variants)
• Autosomal recessive spinocerebellar ataxia 16;Spinocerebellar ataxia 48 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the STUB1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				23		23
missense	5	5	41	4		55
nonsense	2	3	2			7
start loss						0
frameshift	5	6	1			12
inframe indel		2				2
splice donor/acceptor (+/-2bp)		1				1
splice region			2	1	1	4
non coding		2	3	10	9	24
Total	12	19	47	37	9

Highest pathogenic variant AF is 0.0000156

Variants in STUB1

This is a list of pathogenic ClinVar variants found in the STUB1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
16-680226-G-C			Benign (May 18, 2021)
16-680430-C-T			Likely benign (May 22, 2021)
16-680540-G-A			Likely benign (Oct 03, 2022)
16-680550-G-A		Inborn genetic diseases	Uncertain significance (Apr 07, 2023)
16-680556-G-A			Uncertain significance (Sep 01, 2022)
16-680568-G-T			Uncertain significance (Aug 09, 2022)
16-680569-C-T			Uncertain significance (Jun 22, 2023)
16-680577-G-A			Uncertain significance (Jan 24, 2023)
16-680582-C-T			Likely benign (Jul 01, 2022)
16-680585-C-A			Likely benign (May 05, 2022)
16-680585-C-G			Likely benign (Nov 24, 2022)
16-680585-C-T		STUB1-related disorder	Likely benign (Mar 22, 2021)
16-680588-GA-G			Pathogenic (Oct 23, 2020)
16-680601-G-A			Uncertain significance (Dec 01, 2022)
16-680622-G-A		Spinocerebellar ataxia 48	Pathogenic (Jan 04, 2021)
16-680626-A-G			Uncertain significance (Dec 01, 2019)
16-680629-G-C			Uncertain significance (Jun 28, 2022)
16-680632-T-C			Uncertain significance (-)
16-680641-G-A			Uncertain significance (Jul 03, 2019)
16-680659-C-A		Spinocerebellar ataxia 48	Uncertain significance (Jan 03, 2022)
16-680668-G-A		not specified	Uncertain significance (Apr 10, 2023)
16-680670-T-G			Uncertain significance (Jan 26, 2023)
16-680671-A-G			Conflicting classifications of pathogenicity (Nov 19, 2023)
16-680679-G-A		Spinocerebellar ataxia 48	Uncertain significance (Jun 19, 2019)
16-680830-C-T			Benign (Sep 25, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
STUB1	protein_coding	protein_coding	ENST00000219548	7	2647

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0187	0.978	125645	0	13	125658	0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.16	143	188	0.761	0.0000118	1977
Missense in Polyphen		27	70.297	0.38409		712
Synonymous	-2.79	111	79.4	1.40	0.00000537	552
Loss of Function	2.54	6	17.4	0.344	0.00000102	180

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000153	0.000152
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000449	0.0000440
Middle Eastern	0.000109	0.000109
South Asian	0.000103	0.0000980
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;Regulation of PTEN stability and activity;RNA Polymerase II Transcription;Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation;Downregulation of ERBB2 signaling;PTEN Regulation;PIP3 activates AKT signaling;Signaling by ERBB2;Signaling by Receptor Tyrosine Kinases;Signaling by TGF-beta Receptor Complex;Signaling by TGF-beta family members;Downregulation of TGF-beta receptor signaling;TGF-beta receptor signaling activates SMADs;Intracellular signaling by second messengers;Alpha-synuclein signaling;Regulation of RUNX2 expression and activity (Consensus)

Recessive Scores

• pRec: 0.479

Intolerance Scores

• loftool: 0.503
• rvis_EVS: -0.27
• rvis_percentile_EVS: 34.32

Haploinsufficiency Scores

• pHI: 0.415
• hipred: Y
• hipred_score: 0.765
• ghis: 0.504

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.975

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Stub1
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); renal/urinary system phenotype; immune system phenotype; homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; muscle phenotype

Gene ontology

• Biological process: protein polyubiquitination;response to ischemia;DNA repair;ubiquitin-dependent protein catabolic process;protein quality control for misfolded or incompletely synthesized proteins;protein ubiquitination;ubiquitin-dependent ERAD pathway;negative regulation of transforming growth factor beta receptor signaling pathway;ubiquitin-dependent SMAD protein catabolic process;endoplasmic reticulum unfolded protein response;positive regulation of protein ubiquitination;regulation of protein stability;regulation of glucocorticoid metabolic process;negative regulation of protein binding;positive regulation of proteasomal ubiquitin-dependent protein catabolic process;cellular response to heat;ERBB2 signaling pathway;proteasome-mediated ubiquitin-dependent protein catabolic process;positive regulation of ubiquitin-protein transferase activity;protein maturation;protein autoubiquitination;chaperone-mediated autophagy;protein K63-linked ubiquitination;cellular response to misfolded protein;cellular response to hypoxia;positive regulation of chaperone-mediated protein complex assembly
• Cellular component: ubiquitin ligase complex;nucleus;nucleoplasm;cytoplasm;endoplasmic reticulum;cytosol;Z disc;ubiquitin conjugating enzyme complex;nuclear inclusion body;chaperone complex
• Molecular function: G protein-coupled receptor binding;ubiquitin-protein transferase activity;protein binding;enzyme binding;kinase binding;Hsp70 protein binding;protein binding, bridging;TPR domain binding;heat shock protein binding;ubiquitin protein ligase binding;ubiquitin-ubiquitin ligase activity;protein homodimerization activity;SMAD binding;tau protein binding;chaperone binding;misfolded protein binding;Hsp90 protein binding;ubiquitin protein ligase activity