UBA1

protein-coding

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

Gene summary

The protein encoded by this gene catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation. This gene complements an X-linked mouse temperature-sensitive defect in DNA synthesis, and thus may function in DNA repair. It is part of a gene cluster on chromosome Xp11.23. Alternatively spliced transcript variants that encode the same protein have been described. [provided by RefSeq, Jul 2008]

Previous symbols:

A1S9T
GXP1
UBE1

MANE transcript

NM_003334.4

Inheritance

ClinVar variants

P:5U:392B:240

Top phenotype

VEXAS syndrome

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chrX:47,190,861-47,215,128

External References & Databases

Ensembl (ENSG00000130985)

Transcript & Mutation Effects

hg38 • Region Span ~24.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

inflammatory diseaseNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0021166

Submitter: Ambry Genetics

infantile-onset X-linked spinal muscular atrophySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010532

Submitter: Labcorp Genetics (formerly Invitae)

infantile-onset X-linked spinal muscular atrophyMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010532

Submitter: Ambry Genetics

infantile-onset X-linked spinal muscular atrophySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010532

Submitter: Orphanet

infantile-onset X-linked spinal muscular atrophySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010532

Submitter: Genomics England PanelApp

infantile-onset X-linked spinal muscular atrophySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010532

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

VEXAS syndromeXL

Manifestation: Allergy/Immunology/Infectious; Hematologic; Musculoskeletal; Neurologic; Oncologic

Intervention: Allergy/Immunology/Infectious; Hematologic; Oncologic

Rationale: 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

Comments: Somatic variants can cause VEXAS syndrome, a muti-system autoinflammatory disorder

Refs: 18179898; 33108101; 34048852; 34077651; 34077652; 34077653

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UBA1 variants in ClinVar

8 Conditions Cataloged

Infantile-onset X-linked spinal muscular atrophyTotal: 586

Inborn genetic diseasesTotal: 130

not providedTotal: 114

not specifiedTotal: 38

UBA1-related disorderTotal: 23

VEXAS syndromeTotal: 11

VEXASTotal: 3

Congenital portosystemic shuntTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003334.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			27 clinvar	166 clinvar	21 clinvar	214
missense	3 clinvar	2 clinvar	322 clinvar	40 clinvar	13 clinvar	380
nonsense			7 clinvar			7
start loss			2 clinvar			2
frameshift						0
splice donor/acceptor (+/-2bp)			34 clinvar			34
Total	3	2	392	206	34	637

Highest pathogenic variant AF is 0.0000018211718

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 181 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003334.4	RefSeq	NP_003325.2	25	MANE Select
ENST00000335972.11	Ensembl	ENSP00000338413.6	25	MANE Select
NM_001440807.1	RefSeq	NP_001427736.1	26	Standard
NM_001440809.1	RefSeq	NP_001427738.1	26	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
uba1	Danio rerio	Structure: motor neuron Quality: process quality abnormal

Gene / Model

Organism

Observed Phenotype

uba1

Danio rerio

Structure: motor neuron

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquitin mediated proteolysis - Homo sapiens (human)
Parkinson,s disease - Homo sapiens (human)
Proteasome Degradation
Parkin-Ubiquitin Proteasomal System pathway
Parkinsons Disease Pathway

Biological Process

cellular response to DNA damage stimulus
protein ubiquitination
protein modification by small protein conjugation

Molecular Function

RNA binding
ubiquitin activating enzyme activity
protein binding
ATP binding

Cellular Component

heterochromatin
nucleus
nucleoplasm
cytoplasm
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000335972
Coding exons: 25
Length: 24268
Individuals with no LoFs: 125660
Homozygous LoFs: 1
Heterozygous LoFs: 0
Defined: 125661
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.48	248	457	0.543	0.0000402	6899
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0.00022	0.00016	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.361

Intolerance Scores

LoFtool: 0.342
RVIS EVS: -0.22
RVIS percentile EVS: 37.54

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.822

Gene Damage Prediction

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