UBA3

Chr 3

ubiquitin like modifier activating enzyme 3

Also known as: NAE2, UBE1C, hUBA3

NCBI Gene: 9039 ENSG00000144744 UniProt: Q8TBC4

The UBA3 protein serves as the catalytic subunit of an E1 enzyme that activates NEDD8, a ubiquitin-like protein essential for cell cycle progression and regulation of protein degradation pathways. Mutations cause autosomal recessive developmental delay with seizures and dysmorphic features, typically presenting in infancy or early childhood. This gene shows significant constraint against loss-of-function variants (LOEUF 0.405), indicating that complete loss of UBA3 function is likely incompatible with normal development.

ResearchSummary from RefSeq, UniProt

The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes a member of the E1 ubiquitin-activating enzyme family. The encoded enzyme associates with AppBp1, an amyloid beta precursor protein binding protein, to form a heterodimer, and then the enzyme complex activates NEDD8, a ubiquitin-like protein, which regulates cell division, signaling and embryogenesis. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.41

LOEUF

—

Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.504

Z-score 4.14

OE 0.22 (0.12–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.17Z-score

OE missense 0.79 (0.70–0.89)

187 obs / 237.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.12–0.41)

0≤0.351.4

Missense OE?0.79 (0.70–0.89)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 7 / 32.5Missense obs/exp: 187 / 237.5Syn Z: 0.67

Background carrier burden — how many people carry a rare variant somewhere in UBA3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

559 rare PASS variants

Rare truncating (LoF)

1 in 5,700

58 rare PASS variants

Rare synonymous (reference)

1 in 160

224 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for UBA3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 180	1 in 5,400
South Asian	~43k	1 in 100	1 in 7,400
Remaining (unassigned)	~30k	1 in 160	≈ 1 in 9,900
European (Finnish)	~27k	1 in 450	≈ 1 in 6,300
Admixed American	~22k	1 in 170	≈ 1 in 4,500
African / African American	~21k	1 in 250	1 in 2,300
East Asian	~20k	1 in 160	1 in 3,800
Ashkenazi Jewish	~13k	1 in 380	none seen
Middle Eastern	~2,884	1 in 250	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 18 coding exons well covered in gnomAD exomes; exons 4, 5, 8, 18 marginal. Genomes: all 18.? see exons ↓