UBE4A

Chr 11

ubiquitination factor E4A

This protein functions as a ubiquitin ligase that mediates polyubiquitin chain assembly and plays a critical role in chromosome condensation and separation through polyubiquitination of substrates. Biallelic mutations cause autosomal recessive neurodevelopmental disorder with hypotonia and gross motor and speech delay. The gene shows significant constraint against loss-of-function variants (LOEUF 0.388), indicating that such variants are likely pathogenic when present in homozygous or compound heterozygous state.

ResearchSummary from RefSeq, OMIM, UniProt

Ubiquitin-protein ligase that probably functions as an E3 ligase in conjunction with specific E1 and E2 ligases. May also function as an E4 ligase mediating the assembly of polyubiquitin chains on substrates ubiquitinated by another E3 ubiquitin ligase. Mediates 'Lys-48'-linked polyubiquitination of substrates

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtNeurodevelopmental disorder with hypotonia and gross motor and speech delay

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.39

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (2)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

pLI 0.109

Z-score 5.11

OE 0.24 (0.16–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.21Z-score

OE missense 0.74 (0.69–0.81)

436 obs / 586.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.24 (0.16–0.39)

0≤0.351.4

Missense OE?0.74 (0.69–0.81)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 13 / 53.3Missense obs/exp: 436 / 586.6Syn Z: 1.35

Background carrier burden — how many people carry a rare variant somewhere in UBE4A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 64

1,146 rare PASS variants

Rare truncating (LoF)

1 in 920

111 rare PASS variants

Rare synonymous (reference)

1 in 120

434 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for UBE4A. 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 79	1 in 1,100
South Asian	~43k	1 in 58	1 in 490
Remaining (unassigned)	~30k	1 in 53	1 in 1,300
European (Finnish)	~27k	1 in 150	1 in 830
Admixed American	~22k	1 in 52	1 in 560
African / African American	~21k	1 in 61	1 in 310
East Asian	~20k	1 in 59	1 in 680
Ashkenazi Jewish	~13k	1 in 300	1 in 730
Middle Eastern	~2,884	1 in 85	1 in 450

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 19 of 19 coding exons well covered in gnomAD exomes. Genomes: 18 of 19 (exon 15 below).? see exons ↓