UBE3B

Summary

UBE3B (ubiquitin protein ligase E3B, HGNC:13478) is a protein-coding gene on chromosome 12q24.11, encoding Ubiquitin-protein ligase E3B (Q7Z3V4). E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.

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.

Source: NCBI Gene 89910 — RefSeq curated summary.

At a glance

• Gene–disease (curated): oculocerebrofacial syndrome, Kaufman type (Definitive, ClinGen)
• GWAS associations: 30
• Clinical variants (ClinVar): 584 total — 43 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 92
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_130466

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13478
Approved symbol	UBE3B
Name	ubiquitin protein ligase E3B
Location	12q24.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000151148
Ensembl biotype	protein_coding
OMIM	608047
Entrez	89910

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 14 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000340074, ENST00000342494, ENST00000434735, ENST00000449510, ENST00000535900, ENST00000536398, ENST00000537063, ENST00000538070, ENST00000539584, ENST00000539599, ENST00000539843, ENST00000540230, ENST00000605142, ENST00000861742, ENST00000861743, ENST00000861744, ENST00000861745, ENST00000962216, ENST00000962217

RefSeq mRNA: 5 — MANE Select: NM_130466 NM_001270449, NM_001270450, NM_001270451, NM_130466, NM_183415

CCDS: CCDS58277, CCDS9129

Canonical transcript exons

ENST00000342494 — 28 exons

Exon	Start	End
ENSE00001368402	109481637	109481742
ENSE00001384874	109534591	109536702
ENSE00002225203	109483861	109483981
ENSE00002262084	109489919	109490004
ENSE00002264171	109501371	109501534
ENSE00002281798	109497818	109497923
ENSE00002283647	109499633	109499810
ENSE00002297844	109491045	109491127
ENSE00002309008	109477634	109478109
ENSE00002313772	109488572	109488668
ENSE00002314884	109486012	109486071
ENSE00002319951	109509596	109509714
ENSE00002322501	109486471	109486575
ENSE00002323171	109498233	109498353
ENSE00003459025	109523978	109524115
ENSE00003473837	109483531	109483712
ENSE00003509151	109530547	109530658
ENSE00003510749	109521441	109521551
ENSE00003522371	109521148	109521324
ENSE00003530212	109529890	109530072
ENSE00003532411	109533466	109533558
ENSE00003537357	109526358	109526416
ENSE00003545225	109511204	109511303
ENSE00003578284	109507564	109507735
ENSE00003594233	109510344	109510458
ENSE00003629185	109516765	109516884
ENSE00003659643	109524438	109524503
ENSE00003660828	109503023	109503190

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 93.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.4389 / max 88.6392, expressed in 1805 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
127946	11.7321	1804
127945	0.6829	407
127948	0.0180	6
206889	0.0059	4

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	93.36	gold quality
secondary oocyte	CL:0000655	93.07	gold quality
frontal pole	UBERON:0002795	92.26	gold quality
endometrium epithelium	UBERON:0004811	92.23	gold quality
endothelial cell	CL:0000115	91.72	gold quality
Brodmann (1909) area 10	UBERON:0013541	91.00	gold quality
paraflocculus	UBERON:0005351	90.34	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.68	gold quality
stromal cell of endometrium	CL:0002255	89.47	gold quality
gastrocnemius	UBERON:0001388	89.25	gold quality
muscle of leg	UBERON:0001383	89.16	gold quality
tongue squamous epithelium	UBERON:0006919	89.14	gold quality
heart left ventricle	UBERON:0002084	89.12	gold quality
adrenal tissue	UBERON:0018303	89.06	gold quality
cardiac ventricle	UBERON:0002082	88.96	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	88.43	gold quality
apex of heart	UBERON:0002098	88.38	gold quality
rectum	UBERON:0001052	88.35	gold quality
lower esophagus mucosa	UBERON:0035834	88.14	gold quality
lower esophagus	UBERON:0013473	88.05	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.04	gold quality
right atrium auricular region	UBERON:0006631	87.86	gold quality
muscle organ	UBERON:0001630	87.82	gold quality
heart	UBERON:0000948	87.78	gold quality
middle frontal gyrus	UBERON:0002702	87.55	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.48	gold quality
esophagus	UBERON:0001043	87.41	gold quality
mucosa of stomach	UBERON:0001199	87.37	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.32	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.71

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

83 targeting UBE3B, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-7-5P	99.67	70.53	1809

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 15)

• UBE3B is a novel E3 ligase, with a HECT-domain which constitutes the active site for ubiquitin transfer (PMID:12837265)
• the apparent occurrence of an unusual TG 3’ splice site in intron 25 is discussed (PMID:17672918)
• Our data reveal the pleiotropic effects of UBE3B deficiency and reinforce the physiological importance of ubiquitination in neuronal development and function in mammals. (PMID:23200864)
• data provide evidence that Kaufman oculocerebrofacial syndrome is caused by UBE3B loss of function, and further demonstrate the impact of misregulation of protein ubiquitination on development and growth. (PMID:23687348)
• UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome named the Kaufman oculocerebrofacial syndrome (PMID:24615390)
• UBE3B encodes a widely expressed protein ubiquitin ligase E3B, which, when mutated in both alleles, causes Kaufman oculocerebrofacial syndrome. (PMID:25691420)
• The E3 ligase activity of UBE3B is regulated by its interaction with calmodulin via the N-terminal IQ domain. (PMID:28003368)
• studies demonstrate that UBE3B is an E3 ubiquitin ligase and reveal that the enzyme is regulated by calmodulin. Furthermore, the modulation of UBE3B via calmodulin and calcium implicates a role for calcium signaling in mitochondrial protein ubiquitylation, protein turnover, and disease (PMID:28003368)
• Sanger sequencing was negative for the DOORS syndrome gene TBC1D24 but exome sequencing identified a homozygous deletion in UBE3B (NM_183415:c.3139_3141del, p.1047_1047del) located within the terminal portion of the HECT domain (PMID:28003643)
• we present four patients with five novel UBE3B mutations and propose the inclusion of clinical features to the characteristics of Kaufman oculocerebrofacial syndrome, including prominence of the cheeks and limb anomalies. (PMID:29160006)
• Blepharophimosis-ptosis-intellectual disability syndrome: A report of nine Egyptian patients with further expansion of phenotypic and mutational spectrum. (PMID:32949109)
• TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation. (PMID:33298911)
• UBE3B promotes breast cancer progression by antagonizing HIF-2alpha degradation. (PMID:37783786)
• Novel UBE3B mutations: report of eight patients with Kaufman oculocerebrofacial syndrome with additional clinical findings from a highly consanguineous population. (PMID:38410982)
• VHL suppresses UBE3B-mediated breast tumor growth and metastasis. (PMID:38914543)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ube3b	ENSDARG00000061960
mus_musculus	Ube3b	ENSMUSG00000029577
rattus_norvegicus	Ube3b	ENSRNOG00000047219
drosophila_melanogaster	CG5087	FBGN0035953
caenorhabditis_elegans		WBGENE00003898

Paralogs (24): HECW1 (ENSG00000002746), UBE3C (ENSG00000009335), NEDD4L (ENSG00000049759), NEDD4 (ENSG00000069869), ITCH (ENSG00000078747), HACE1 (ENSG00000085382), HUWE1 (ENSG00000086758), HECTD1 (ENSG00000092148), UBR5 (ENSG00000104517), SMURF2 (ENSG00000108854), UBE3A (ENSG00000114062), AREL1 (ENSG00000119682), WWP1 (ENSG00000123124), HERC2 (ENSG00000128731), HECW2 (ENSG00000138411), HERC3 (ENSG00000138641), HERC6 (ENSG00000138642), HERC5 (ENSG00000138646), HERC4 (ENSG00000148634), TRIP12 (ENSG00000153827), HECTD2 (ENSG00000165338), HECTD4 (ENSG00000173064), WWP2 (ENSG00000198373), SMURF1 (ENSG00000198742)

Protein

Protein identifiers

Ubiquitin-protein ligase E3B — Q7Z3V4 (reviewed: Q7Z3V4)

Alternative names: HECT-type ubiquitin transferase E3B

All UniProt accessions (4): Q7Z3V4, F5H5T5, F5H6D6, S4R3H8

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Ubiquitinates BCKDK and targets it for degradation, thereby regulating various metabolic processes. Involved in the positive regulation of neurite branching in hippocampal neurons and the control of neuronal spine number and morphology, through the ubiquitination of PPP3CC.

Subcellular location. Postsynaptic density.

Tissue specificity. Widely expressed.

Disease relevance. Kaufman oculocerebrofacial syndrome (KOS) [MIM:244450] A syndrome characterized by blepharophimosis, ptosis, mild upslanting of the palpebral fissures, epicanthus, ectodermal anomalies, developmental delay, and severe intellectual disability with absent speech. Proportionate growth retardation with a small head circumference/microcephaly, congenital malformations, muscular hypotonia, anomalies on brain imaging with hypoplasia of the corpus callosum, and low cholesterol levels are variably present. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Major isoform.

Isoforms (3)

UniProt ID	Names	Canonical?
Q7Z3V4-1	1, UBE3B_v1	yes
Q7Z3V4-2	2, UBE3B_v2
Q7Z3V4-3	3

RefSeq proteins (5): NP_001257378, NP_001257379, NP_001257380, NP_569733, NP_904324 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000048	IQ_motif_EF-hand-BS	Binding_site
IPR000569	HECT_dom	Domain
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR044611	E3A/B/C-like	Family

Pfam: PF00632

Enzyme classification (BRENDA):

• EC 2.3.2.26 — HECT-type E3 ubiquitin transferase (BRENDA: 14 organisms, 64 substrates, 19 inhibitors, 5 Km, 5 kcat entries)
• EC 2.3.2.B11 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBC5B]-L-LYSINE	0.0046–0.037	5

UniProt features (28 total): sequence variant 14, sequence conflict 4, splice variant 4, domain 2, modified residue 2, chain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z3V4-F1	85.14	0.56

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 1036 (glycyl thioester intermediate)

Post-translational modifications (2): 1, 419

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 367 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_SYNAPSE_ASSEMBLY, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, PATIL_LIVER_CANCER, CHANG_IMMORTALIZED_BY_HPV31_DN, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_REGULATION_OF_SYNAPSE_ASSEMBLY, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION

GO Biological Process (4): protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), regulation of postsynapse assembly (GO:0150052), protein ubiquitination (GO:0016567)

GO Molecular Function (4): ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (5): mitochondrion (GO:0005739), postsynaptic density (GO:0014069), glutamatergic synapse (GO:0098978), synapse (GO:0045202), postsynapse (GO:0098794)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	2
synapse	2
modification-dependent protein catabolic process	1
regulation of synapse assembly	1
postsynapse assembly	1
regulation of postsynapse organization	1
protein modification by small protein conjugation	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
asymmetric synapse	1
postsynaptic specialization	1
cell junction	1
cellular anatomical structure	1

Protein interactions and networks

STRING

988 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UBE3B	TRPV4	Q9HBA0	797
UBE3B	ATP2B1	P20020	779
UBE3B	ZNF18	P17022	717
UBE3B	ATP2A2	P16614	678
UBE3B	SLC17A8	Q8NDX2	639
UBE3B	NCKAP5L	Q9HCH0	579
UBE3B	MROH8	Q9H579	494
UBE3B	TRIP12	Q14669	470
UBE3B	RCC1L	Q96I51	447
UBE3B	ANKRD11	Q6UB99	427
UBE3B	ZNF462	Q96JM2	425
UBE3B	PUDP	Q08623	414
UBE3B	RNF216	Q9NWF9	412
UBE3B	SDE2	Q6IQ49	401
UBE3B	GART	P22102	398

IntAct

47 interactions, top by confidence:

A	B	Type	Score
NAPA	SNAP23	psi-mi:“MI:0914”(association)	0.780
IFI30	DAPK1	psi-mi:“MI:0914”(association)	0.730
NAPG	NSF	psi-mi:“MI:0914”(association)	0.640
SEC16A	SEC13	psi-mi:“MI:0914”(association)	0.640
UBE3B	CALM1	psi-mi:“MI:0915”(physical association)	0.620
UBE3B	CALM1	psi-mi:“MI:0914”(association)	0.620
DLK1	TCAF2	psi-mi:“MI:0914”(association)	0.530
IFI30	PRC1	psi-mi:“MI:0914”(association)	0.530
VAMP4	SNAP29	psi-mi:“MI:0914”(association)	0.530
UBE3B	MYL12B	psi-mi:“MI:0915”(physical association)	0.500
LIG1	UBE3B	psi-mi:“MI:0915”(physical association)	0.400
MAN1A2	UBE3B	psi-mi:“MI:0915”(physical association)	0.400
ORAI1	UBE3B	psi-mi:“MI:0915”(physical association)	0.400
SCD5	UBE3B	psi-mi:“MI:0915”(physical association)	0.400
Oxnad1	KPNA6	psi-mi:“MI:0914”(association)	0.350
IQCB1	PCP4L1	psi-mi:“MI:0914”(association)	0.350
BET1L	GOSR1	psi-mi:“MI:0914”(association)	0.350
CALM1	MYO1C	psi-mi:“MI:0914”(association)	0.350
CALM2	MYO1C	psi-mi:“MI:0914”(association)	0.350
CAPZB	ENAH	psi-mi:“MI:0914”(association)	0.350
EDC4	ALDH18A1	psi-mi:“MI:0914”(association)	0.350
ELOVL1	LDHA	psi-mi:“MI:0914”(association)	0.350
GPAT3	EIF4G3	psi-mi:“MI:0914”(association)	0.350
LMNB1	SUPT5H	psi-mi:“MI:0914”(association)	0.350
SCD	TTC27	psi-mi:“MI:0914”(association)	0.350
SNF8	TNPO2	psi-mi:“MI:0914”(association)	0.350
TOP2A	RPL6	psi-mi:“MI:0914”(association)	0.350
UBB	RNF40	psi-mi:“MI:0914”(association)	0.350

BioGRID (86): UBE3B (Affinity Capture-MS), UBE3B (Affinity Capture-MS), UBE3B (Co-fractionation), UBE3B (Co-fractionation), UBE3B (Synthetic Lethality), UBE3B (Affinity Capture-MS), UBE3B (Biochemical Activity), CALM3 (Affinity Capture-MS), CALM3 (Affinity Capture-Western), CALM3 (Proximity Label-MS), UBE3B (Affinity Capture-MS), UBE3B (Affinity Capture-MS), UBE3B (Affinity Capture-MS), UBE3B (Reconstituted Complex), UBE3B (Affinity Capture-MS)

ESM2 similar proteins: A2AGL3, B0LPN4, E9PZQ0, E9Q401, F1LMY4, F1Q8X5, P0C7A6, P11716, P11881, P16960, P21817, P29994, P29995, P30957, P42694, P48553, Q0VEJ0, Q14571, Q14643, Q15413, Q1LVW0, Q24498, Q28C34, Q3TLI0, Q5F361, Q5RCP7, Q6NRC7, Q6NRD0, Q6NYU2, Q6QI06, Q6R327, Q7SXV1, Q7Z3V4, Q7ZUV0, Q7ZYD9, Q80UK0, Q86VW0, Q8BHL5, Q8BIK4, Q8BWW9

Diamond homologs: A0A8C0NGY6, A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B8N7E5, D3ZBM7, D6C652, E1B7Q7, E1C656, F1LP64, F1N6G5, F8W2M1, G0S9J5, G5E870, H2LBU8, O00308, O08759, O13834, O14326, O15033, P39940, P40985, P46934, P46935, P46937, P46938, P51593, P53119, Q03280, Q05086, Q08CZ0, Q09291, Q0CCL1, Q14669, Q15034, Q15386, Q1K9C4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	UBE3B	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 69 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Intra-Golgi traffic	7	31.3×	1e-06
COPII-mediated vesicle transport	5	14.1×	2e-03
ER to Golgi Anterograde Transport	6	13.7×	6e-04
Transport to the Golgi and subsequent modification	7	12.4×	2e-04
COPI-mediated anterograde transport	6	11.4×	2e-03
Intra-Golgi and retrograde Golgi-to-ER traffic	6	10.8×	2e-03
Membrane Trafficking	13	8.3×	1e-06
Vesicle-mediated transport	13	7.8×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

584 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	43
Likely pathogenic	17
Uncertain significance	220
Likely benign	221
Benign	38

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1032375	NM_130466.4(UBE3B):c.2228_2229del (p.Val742_Phe743insTer)	Pathogenic
1323733	NM_130466.4(UBE3B):c.2302del (p.His768fs)	Pathogenic
1323734	NM_130466.4(UBE3B):c.343-1G>A	Pathogenic
1676841	NM_130466.4(UBE3B):c.3065_3078delinsC (p.Arg1022fs)	Pathogenic
1683785	NM_130466.4(UBE3B):c.2061del (p.Ser688fs)	Pathogenic
1684269	NM_130466.4(UBE3B):c.2624dup (p.Asn875fs)	Pathogenic
1691089	NM_130466.4(UBE3B):c.2335G>A (p.Gly779Arg)	Pathogenic
1691090	NM_130466.4(UBE3B):c.2098C>T (p.Gln700Ter)	Pathogenic
1710251	NM_130466.4(UBE3B):c.2547C>A (p.Tyr849Ter)	Pathogenic
1972108	NM_130466.4(UBE3B):c.1167G>A (p.Trp389Ter)	Pathogenic
1992764	NM_130466.4(UBE3B):c.2863_2885dup (p.Asp963fs)	Pathogenic
2037898	NM_130466.4(UBE3B):c.58C>T (p.Arg20Ter)	Pathogenic
225041	NM_130466.4(UBE3B):c.61G>T (p.Glu21Ter)	Pathogenic
2412802	NM_130466.4(UBE3B):c.1957-1G>A	Pathogenic
2430959	NM_130466.4(UBE3B):c.1622+1G>A	Pathogenic
2500941	NM_130466.4(UBE3B):c.2569-2A>C	Pathogenic
2572570	NM_130466.4(UBE3B):c.739_742del (p.Asp247fs)	Pathogenic
2693281	NM_130466.4(UBE3B):c.1197_1206del (p.Phe398_Cys399insTer)	Pathogenic
2734859	NM_130466.4(UBE3B):c.262del (p.Arg88fs)	Pathogenic
280736	NM_130466.4(UBE3B):c.941-1G>A	Pathogenic
280737	NM_130466.4(UBE3B):c.256del (p.Leu86fs)	Pathogenic
2886463	NM_130466.4(UBE3B):c.2675_2678del (p.Ile892fs)	Pathogenic
2900215	NM_130466.4(UBE3B):c.1806C>G (p.Tyr602Ter)	Pathogenic
2901932	NM_130466.4(UBE3B):c.469C>T (p.Arg157Ter)	Pathogenic
2910863	NM_130466.4(UBE3B):c.2737C>T (p.Arg913Ter)	Pathogenic
3062052	NM_130466.4(UBE3B):c.518C>A (p.Ser173Ter)	Pathogenic
3647086	NM_130466.4(UBE3B):c.1417dup (p.Thr473fs)	Pathogenic
3650092	NM_130466.4(UBE3B):c.1018C>T (p.Gln340Ter)	Pathogenic
3710111	NM_130466.4(UBE3B):c.1443dup (p.Leu482fs)	Pathogenic
4085145	NM_130466.4(UBE3B):c.161+1G>A	Pathogenic

SpliceAI

4512 predictions. Top by Δscore:

Variant	Effect	Δscore
12:109481625:T:TA	acceptor_gain	1.0000
12:109483529:A:AG	acceptor_gain	1.0000
12:109483529:A:C	acceptor_loss	1.0000
12:109483529:AG:A	acceptor_gain	1.0000
12:109483529:AGG:A	acceptor_gain	1.0000
12:109483530:G:GC	acceptor_gain	1.0000
12:109483530:GG:G	acceptor_gain	1.0000
12:109483530:GGG:G	acceptor_gain	1.0000
12:109483530:GGGT:G	acceptor_gain	1.0000
12:109483530:GGGTT:G	acceptor_gain	1.0000
12:109483710:CAGG:C	donor_loss	1.0000
12:109483711:AGG:A	donor_loss	1.0000
12:109483713:G:C	donor_loss	1.0000
12:109483713:G:GG	donor_gain	1.0000
12:109483714:T:A	donor_loss	1.0000
12:109483847:A:AG	acceptor_gain	1.0000
12:109483848:C:G	acceptor_gain	1.0000
12:109483856:TCTAG:T	acceptor_loss	1.0000
12:109483857:CTAG:C	acceptor_loss	1.0000
12:109483859:A:AG	acceptor_gain	1.0000
12:109483859:AG:A	acceptor_gain	1.0000
12:109483860:G:GA	acceptor_gain	1.0000
12:109483860:GG:G	acceptor_gain	1.0000
12:109483860:GGA:G	acceptor_gain	1.0000
12:109483860:GGAGA:G	acceptor_gain	1.0000
12:109483973:GATAA:G	donor_gain	1.0000
12:109483979:G:GT	donor_gain	1.0000
12:109483979:GAG:G	donor_gain	1.0000
12:109483979:GAGG:G	donor_loss	1.0000
12:109483982:G:GC	donor_loss	1.0000

AlphaMissense

7027 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:109521211:T:C	F714L	1.000
12:109521212:T:C	F714S	1.000
12:109521213:T:A	F714L	1.000
12:109521213:T:G	F714L	1.000
12:109521237:A:C	E722D	1.000
12:109521237:A:T	E722D	1.000
12:109521241:G:A	G724R	1.000
12:109521241:G:C	G724R	1.000
12:109521242:G:A	G724E	1.000
12:109521247:G:C	D726H	1.000
12:109521248:A:C	D726A	1.000
12:109521248:A:G	D726G	1.000
12:109521248:A:T	D726V	1.000
12:109521249:T:A	D726E	1.000
12:109521249:T:G	D726E	1.000
12:109521256:G:C	G729R	1.000
12:109521256:G:T	G729C	1.000
12:109521257:G:A	G729D	1.000
12:109521267:G:C	K732N	1.000
12:109521267:G:T	K732N	1.000
12:109526401:T:A	V871D	1.000
12:109530572:T:C	F946L	1.000
12:109530574:C:A	F946L	1.000
12:109530574:C:G	F946L	1.000
12:109530603:T:C	L956P	1.000
12:109533466:T:C	F975L	1.000
12:109533468:C:A	F975L	1.000
12:109533468:C:G	F975L	1.000
12:109533475:A:C	S978R	1.000
12:109533477:C:A	S978R	1.000

dbSNP variants (sampled 300 via entrez): RS1000091941 (12:109487834 C>G), RS1000133484 (12:109529710 G>A), RS1000135306 (12:109504402 G>A), RS1000137030 (12:109535605 C>T), RS1000225046 (12:109527899 C>T), RS1000251753 (12:109504753 G>A,C,T), RS1000263735 (12:109500895 C>G), RS1000276621 (12:109484753 G>A), RS1000319930 (12:109494387 T>C), RS1000406604 (12:109490808 T>G), RS1000416115 (12:109546682 G>T), RS1000450619 (12:109533537 C>T), RS1000499756 (12:109493380 T>A), RS1000597960 (12:109479487 G>A), RS1000599462 (12:109499477 A>G)

Disease associations

OMIM: gene MIM:608047 | disease phenotypes: MIM:244450

GenCC curated gene-disease

Disease	Classification	Inheritance
oculocerebrofacial syndrome, Kaufman type	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
oculocerebrofacial syndrome, Kaufman type	Definitive	AR

Mondo (3): oculocerebrofacial syndrome, Kaufman type (MONDO:0009485), intellectual disability (MONDO:0001071), blepharophimosis - intellectual disability syndrome (MONDO:0017393)

Orphanet (3): Oculocerebrofacial syndrome, Kaufman type (Orphanet:2707), Blepharophimosis-intellectual disability syndrome (Orphanet:293642), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

92 total (30 of 92 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000059	Hypoplastic labia majora
HP:0000154	Wide mouth
HP:0000159	Abnormal lip morphology
HP:0000160	Narrow mouth
HP:0000177	Abnormal upper lip morphology
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000384	Preauricular skin tag
HP:0000463	Anteverted nares
HP:0000482	Microcornea
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000506	Telecanthus
HP:0000508	Ptosis
HP:0000543	Optic disc pallor
HP:0000545	Myopia

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST000805_11	HDL cholesterol	3.000000e-06
GCST006052_4	Polymyositis	4.000000e-06
GCST006614_36	Total cholesterol levels	2.000000e-08
GCST008070_128	HDL cholesterol levels	7.000000e-09
GCST008070_55	HDL cholesterol levels	1.000000e-18
GCST008070_96	HDL cholesterol levels	3.000000e-07
GCST008075_170	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-24
GCST008075_223	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	2.000000e-07
GCST008075_49	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-13
GCST008084_118	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	6.000000e-09
GCST008084_2	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	6.000000e-17
GCST008084_216	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	1.000000e-29
GCST008085_155	HDL cholesterol levels in current drinkers	1.000000e-09
GCST008085_60	HDL cholesterol levels in current drinkers	3.000000e-19
GCST008085_87	HDL cholesterol levels in current drinkers	7.000000e-08
GCST010134_6	Non-oily fish consumption	6.000000e-11
GCST010135_11	Oily fish consumption	6.000000e-11
GCST010135_3	Oily fish consumption	7.000000e-17
GCST010140_3	Pork consumption	6.000000e-11
GCST010140_47	Pork consumption	7.000000e-17
GCST010142_62	Fish- and plant-related diet	4.000000e-13
GCST010142_83	Fish- and plant-related diet	4.000000e-08
GCST010142_87	Fish- and plant-related diet	2.000000e-19
GCST010142_94	Fish- and plant-related diet	5.000000e-13
GCST010320_17	PR interval	3.000000e-10
GCST010321_78	PR interval	5.000000e-11
GCST010479_28	Coronary artery disease	1.000000e-10
GCST011346_22	Total cholesterol levels	2.000000e-11
GCST011348_32	High density lipoprotein cholesterol levels	6.000000e-18
GCST90002390_71	Mean corpuscular hemoglobin	2.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0008111	diet measurement
EFO:0004462	PR interval
EFO:0004527	mean corpuscular hemoglobin

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C537013	Kaufman oculocerebrofacial syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	2
sodium arsenite	affects expression, increases expression	2
Benzo(a)pyrene	affects methylation	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	decreases expression	1
ICG 001	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Caffeine	affects phosphorylation	1
Calcium Chloride	decreases activity, decreases reaction, affects binding	1
Dexamethasone	increases expression	1
Methotrexate	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Quercetin	increases expression	1
Silicon Dioxide	decreases expression	1
Cyclosporine	decreases expression	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2K9	Abcam HeLa UBE3B KO 1	Cancer cell line	Female
CVCL_B2KA	Abcam HeLa UBE3B KO 2	Cancer cell line	Female

Clinical trials (associated diseases)

197 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders