UBE3B

Chr 12AR

ubiquitin protein ligase E3B

Also known as: BPIDS, KOS

NCBI Gene: 89910 ENSG00000151148 UniProt: Q7Z3V4 OMIM: 608047

This gene encodes an E3 ubiquitin-protein ligase that transfers ubiquitin to target proteins for degradation and regulates neurite branching and neuronal spine morphology in hippocampal neurons. Biallelic mutations cause Kaufman oculocerebrofacial syndrome, a rare autosomal recessive disorder affecting facial features, eyes, and brain development. The gene is highly constrained against loss-of-function variants (LOEUF 0.545), indicating intolerance to protein-disrupting mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, 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: E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin-protein ligases. This gene encodes a member of the E3 ubiquitin-conjugating enzyme family which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme and transfers the ubiquitin to the targeted substrates. A HECT (homology to E6-AP C-terminus) domain in the C-terminus of the longer isoform of this protein is the catalytic site of ubiquitin transfer and forms a complex with E2 conjugases. Shorter isoforms of this protein which lack the C-terminal HECT domain are therefore unlikely to bind E2 enzymes. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.551 OMIM phenotype

Clinical Summary— UBE3B

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Gene-Disease Validity (ClinGen)

oculocerebrofacial syndrome, Kaufman type · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

71 unique Pathogenic / Likely Pathogenic· 222 VUS of 589 total submissions

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GeneReview available — UBE3B

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.55LOEUF

pLI 0.000

Z-score 4.47

OE 0.39 (0.28–0.55)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.36Z-score

OE missense 0.85 (0.79–0.91)

539 obs / 635.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.39 (0.28–0.55)

0≤0.351.4

Missense OE?0.85 (0.79–0.91)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 24 / 62.0Missense obs/exp: 539 / 635.4Syn Z: 0.86

ClinVar Variant Classifications

589 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44

Likely Pathogenic27

VUS222

Likely Benign226

Benign38

Conflicting6

Pathogenic

Likely Pathogenic

222

VUS

226

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	41	3	0	0	44
Likely Pathogenic	23	4	0	0	27
VUS	0	216	6	0	222
Likely Benign	1	5	93	127	226
Benign	0	3	20	15	38
Conflicting	—				6
Total	65	231	119	142	563

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

9 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap UBE3B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →