UBA1

ubiquitin like modifier activating enzyme 1, the group of Ubiquitin like modifier activating enzymes|Cilia and flagella associated

Basic information

Region (hg38): X:47190860-47215128

Previous symbols: [ "A1S9T", "GXP1", "UBE1" ]

Links

ENSG00000130985 ∙ NCBI:7317 ∙ OMIM:314370 ∙ HGNC:12469 ∙ Uniprot:P22314 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• infantile-onset X-linked spinal muscular atrophy (Strong), mode of inheritance: XL
• infantile-onset X-linked spinal muscular atrophy (Strong), mode of inheritance: XL
• infantile-onset X-linked spinal muscular atrophy (Supportive), mode of inheritance: XL
• inflammatory disease (No Known Disease Relationship), mode of inheritance: Unknown
• infantile-onset X-linked spinal muscular atrophy (Moderate), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
VEXAS syndrome	XL	Allergy/Immunology/Infectious; Hematologic; Oncologic	VEXAS syndrome may involve multisystem inflammatory disease, and medical management (eg, corticosteroids, IL-6 antagonists) have been described as resulting in some benefit; HSCT has been described	Allergy/Immunology/Infectious; Hematologic; Musculoskeletal; Neurologic; Oncologic	18179898; 33108101; 34048852; 34077651; 34077652; 34077653
Somatic variants can cause VEXAS syndrome, a muti-system autoinflammatory disorder

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the UBA1 gene.

• Infantile-onset X-linked spinal muscular atrophy (422 variants)
• not provided (96 variants)
• Inborn genetic diseases (79 variants)
• not specified (33 variants)
• VEXAS syndrome (4 variants)
• UBA1-related condition (4 variants)
• VEXAS (3 variants)
• Infantile-onset X-linked spinal muscular atrophy;VEXAS syndrome (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the UBA1 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			3	121	21	145
missense	1	1	176	15	16	209
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region			12	15	3	30
non coding			6	59	32	97
Total	1	1	186	195	69

Variants in UBA1

This is a list of pathogenic ClinVar variants found in the UBA1 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-47193847-G-A		Infantile-onset X-linked spinal muscular atrophy	Uncertain significance (Jan 13, 2018)
X-47193980-C-T		Infantile-onset X-linked spinal muscular atrophy	Uncertain significance (Jan 12, 2018)
X-47196470-G-A			Likely benign (Dec 01, 2022)
X-47198248-A-G		not specified	Benign (Jan 24, 2024)
X-47198545-A-G			Benign (Aug 14, 2018)
X-47198817-G-A		Infantile-onset X-linked spinal muscular atrophy	Benign (Aug 11, 2023)
X-47198833-C-T		Infantile-onset X-linked spinal muscular atrophy	Uncertain significance (Aug 09, 2022)
X-47198836-G-T		Infantile-onset X-linked spinal muscular atrophy	Uncertain significance (Sep 25, 2021)
X-47198841-C-T		Infantile-onset X-linked spinal muscular atrophy	Benign (Nov 24, 2023)
X-47198856-G-T		Infantile-onset X-linked spinal muscular atrophy	Uncertain significance (Sep 30, 2023)
X-47198858-C-T		Infantile-onset X-linked spinal muscular atrophy	Uncertain significance (Jun 22, 2023)
X-47198859-G-A		Infantile-onset X-linked spinal muscular atrophy	Likely benign (Aug 05, 2022)
X-47198866-A-G		Infantile-onset X-linked spinal muscular atrophy	Uncertain significance (Aug 31, 2022)
X-47198874-C-T		Infantile-onset X-linked spinal muscular atrophy	Likely benign (Jul 19, 2022)
X-47198877-T-G		Infantile-onset X-linked spinal muscular atrophy	Likely benign (Aug 11, 2023)
X-47198878-G-A		Infantile-onset X-linked spinal muscular atrophy	Uncertain significance (Apr 05, 2023)
X-47198883-G-C			Uncertain significance (Jul 18, 2022)
X-47198886-C-T		Infantile-onset X-linked spinal muscular atrophy • UBA1-related disorder	Likely benign (Sep 06, 2022)
X-47198887-G-A		Infantile-onset X-linked spinal muscular atrophy	Uncertain significance (Oct 06, 2021)
X-47198894-C-G		Infantile-onset X-linked spinal muscular atrophy	Uncertain significance (Dec 31, 2021)
X-47198895-C-T		Infantile-onset X-linked spinal muscular atrophy	Likely benign (Oct 17, 2019)
X-47198896-G-A		Infantile-onset X-linked spinal muscular atrophy	Benign (Jan 31, 2020)
X-47198899-G-A		Infantile-onset X-linked spinal muscular atrophy	Uncertain significance (Jan 29, 2019)
X-47198907-G-A		Infantile-onset X-linked spinal muscular atrophy	Conflicting classifications of pathogenicity (Dec 05, 2021)
X-47198908-G-A		Infantile-onset X-linked spinal muscular atrophy	Uncertain significance (Nov 07, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
UBA1	protein_coding	protein_coding	ENST00000335972	25	24268

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	6.38e-7	125660	1	0	125661	0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.48	248	457	0.543	0.0000402	6899
Missense in Polyphen		41	160.54	0.25539		2587
Synonymous	-1.14	206	186	1.11	0.0000165	2134
Loss of Function	6.01	1	44.1	0.0227	0.00000378	610

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000221	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation through the ubiquitin- proteasome system (PubMed:1606621, PubMed:1447181). Activates ubiquitin by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a ubiquitin-E1 thioester and free AMP (PubMed:1447181). Essential for the formation of radiation- induced foci, timely DNA repair and for response to replication stress. Promotes the recruitment of TP53BP1 and BRCA1 at DNA damage sites (PubMed:22456334). {ECO:0000269|PubMed:1447181, ECO:0000269|PubMed:1606621, ECO:0000269|PubMed:22456334}.
• Disease: DISEASE: Spinal muscular atrophy X-linked 2 (SMAX2) [MIM:301830]: A lethal infantile form of spinal muscular atrophy, a neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. Clinical features include hypotonia, areflexia, and multiple congenital contractures. {ECO:0000269|PubMed:18179898, ECO:0000269|PubMed:23518311}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Ubiquitin mediated proteolysis - Homo sapiens (human);Parkinson,s disease - Homo sapiens (human);Proteasome Degradation;Parkin-Ubiquitin Proteasomal System pathway;Parkinsons Disease Pathway;proteasome complex;gamma-aminobutyric acid receptor life cycle pathway;fibrinolysis pathway;Post-translational protein modification;protein ubiquitylation;Metabolism of proteins;Synthesis of active ubiquitin: roles of E1 and E2 enzymes;Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation;sumoylation as a mechanism to modulate ctbp-dependent gene responses;Protein ubiquitination (Consensus)

Recessive Scores

• pRec: 0.361

Intolerance Scores

• loftool: 0.342
• rvis_EVS: -0.22
• rvis_percentile_EVS: 37.54

Haploinsufficiency Scores

• pHI: 0.521
• hipred: Y
• hipred_score: 0.802
• ghis: 0.520

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.822

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Uba1

Zebrafish Information Network

• Gene name: uba1
• Affected structure: motor neuron
• Phenotype tag: abnormal
• Phenotype quality: process quality

Gene ontology

• Biological process: cellular response to DNA damage stimulus;protein ubiquitination;protein modification by small protein conjugation
• Cellular component: heterochromatin;nucleus;nucleoplasm;cytoplasm;mitochondrion;lysosomal membrane;cytosol;endosome membrane;desmosome;rough endoplasmic reticulum membrane;extracellular exosome
• Molecular function: RNA binding;ubiquitin activating enzyme activity;protein binding;ATP binding