UBE3A

ubiquitin protein ligase E3A, the group of HECT domain containing

Basic information

Region (hg38): 15:25333728-25439051

Previous symbols: [ "EPVE6AP", "HPVE6A" ]

Links

ENSG00000114062 ∙ NCBI:7337 ∙ OMIM:601623 ∙ HGNC:12496 ∙ Uniprot:Q05086 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Angelman syndrome (Definitive), mode of inheritance: Autosomal dominant inheritance with paternal imprinting
• Angelman syndrome (Strong), mode of inheritance: AD
• Angelman syndrome (Definitive), mode of inheritance: AD
• Angelman syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Angelman syndrome	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	8988171; 8988172; 9546330; 10196695; 11748306; 12210318; 15150776; 20034088; 20933619; 21072004; 21204213; 21362313; 21397058; 22065487

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the UBE3A gene.

• Angelman syndrome (87 variants)
• not provided (47 variants)
• Inborn genetic diseases (9 variants)
• Intellectual disability (3 variants)
• UBE3A-related disorder (3 variants)
• Epileptic encephalopathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the UBE3A gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			8	149	12	169
missense	5	24	264	4	4	301
nonsense	31	7				38
start loss						0
frameshift	75	16				91
inframe indel	4	5	11			20
splice donor/acceptor (+/-2bp)	5	2	1	1		9
splice region			11	14		25
non coding			4	71	27	102
Total	120	54	288	225	43

Variants in UBE3A

This is a list of pathogenic ClinVar variants found in the UBE3A region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
15-25338938-T-C			Likely benign (Sep 15, 2019)
15-25339053-A-ATCCC		Angelman syndrome	Pathogenic (Jun 15, 2004)
15-25339090-CT-C		Angelman syndrome	Uncertain significance (Feb 14, 2014)
15-25339101-CTTCCTTTTTTTTGT-C			Likely benign (Aug 01, 2024)
15-25339114-G-T			Benign (Mar 06, 2020)
15-25339119-ATTTTG-A		Angelman syndrome	Likely benign (Jul 14, 2017)
15-25339119-ATTTTGTTTTG-A			Conflicting classifications of pathogenicity (May 30, 2018)
15-25339119-ATTTTGTTTTGTTTTG-A			Likely benign (Dec 03, 2021)
15-25339124-GT-G			Likely benign (Jan 30, 2018)
15-25339124-GTTTTGTTTTGTTTTA-G			Likely pathogenic (Oct 23, 2020)
15-25339130-TTTTGTTTTAC-T		Angelman syndrome	Pathogenic (Feb 22, 2016)
15-25339133-T-C		Angelman syndrome	Uncertain significance (Jun 15, 2023)
15-25339138-T-A		Angelman syndrome	Pathogenic (Feb 14, 2014)
15-25339138-T-C		not specified • Angelman syndrome • UBE3A-related disorder • Inborn genetic diseases	Benign (Aug 01, 2024)
15-25339141-AGCATGCCAAATCCTTTGGCATACGTGATGGCCTTCAACAATCTCTCTTTAAGTTTTTCTTTGCTTGAG-A		Angelman syndrome	Pathogenic (Feb 14, 2014)
15-25339142-G-A		Angelman syndrome	Likely benign (Aug 06, 2021)
15-25339147-C-T		Angelman syndrome	Conflicting classifications of pathogenicity (Jan 15, 2014)
15-25339148-C-CA		Angelman syndrome	Pathogenic (Feb 08, 2013)
15-25339152-T-A		Angelman syndrome	Likely benign (Aug 05, 2022)
15-25339151-A-ATCCTT		Angelman syndrome	Likely pathogenic (Sep 01, 2021)
15-25339158-G-A		Inborn genetic diseases	Likely benign (May 31, 2017)
15-25339159-GC-G			Likely pathogenic (Nov 30, 2016)
15-25339164-C-G		Angelman syndrome	Likely benign (Mar 04, 2023)
15-25339164-C-T		not specified • Angelman syndrome	Benign/Likely benign (Jun 01, 2024)
15-25339165-G-A		Angelman syndrome	Uncertain significance (Jan 20, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
UBE3A	protein_coding	protein_coding	ENST00000397954	11	101748

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000199	125706	0	3	125709	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.40	191	455	0.419	0.0000238	5818
Missense in Polyphen		12	108.74	0.11035		1412
Synonymous	0.509	155	163	0.949	0.00000869	1593
Loss of Function	5.23	3	37.6	0.0799	0.00000206	516

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000556	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.00000885	0.00000880
Middle Eastern	0.0000556	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates (PubMed:10373495, PubMed:16772533, PubMed:19204938, PubMed:19233847, PubMed:19325566, PubMed:19591933, PubMed:22645313, PubMed:24273172, PubMed:24728990). Several substrates have been identified including the ARNTL/BMAL1, ARC, RAD23A and RAD23B, MCM7 (which is involved in DNA replication), annexin A1, the PML tumor suppressor, and the cell cycle regulator CDKN1B (PubMed:10373495, PubMed:19204938, PubMed:19325566, PubMed:19591933, PubMed:22645313, PubMed:24728990). Additionally, may function as a cellular quality control ubiquitin ligase by helping the degradation of the cytoplasmic misfolded proteins (PubMed:19233847). Finally, UBE3A also promotes its own degradation in vivo. Plays an important role in the regulation of the circadian clock: involved in the ubiquitination of the core clock component ARNTL/BMAL1, leading to its proteasomal degradation (PubMed:24728990). Acts as transcriptional coactivator of progesterone receptor PGR upon progesterone hormone activation (PubMed:16772533). Acts as a regulator of synaptic development by mediating ubiquitination and degradation of ARC (By similarity). Synergizes with WBP2 in enhancing PGR activity (PubMed:16772533). {ECO:0000250|UniProtKB:O08759, ECO:0000269|PubMed:10373495, ECO:0000269|PubMed:16772533, ECO:0000269|PubMed:19204938, ECO:0000269|PubMed:19233847, ECO:0000269|PubMed:19325566, ECO:0000269|PubMed:19591933, ECO:0000269|PubMed:22645313, ECO:0000269|PubMed:24273172, ECO:0000269|PubMed:24728990}.
• Disease: DISEASE: Angelman syndrome (AS) [MIM:105830]: A neurodevelopmental disorder characterized by severe motor and intellectual retardation, ataxia, frequent jerky limb movements and flapping of the arms and hands, hypotonia, seizures, absence of speech, frequent smiling and episodes of paroxysmal laughter, open-mouthed expression revealing the tongue. {ECO:0000269|PubMed:25212744, ECO:0000269|PubMed:9585605}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Ubiquitin mediated proteolysis - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Androgen receptor signaling pathway;MECP2 and Associated Rett Syndrome;Prader-Willi and Angelman Syndrome;Tryptophan metabolism;proteasome complex;gamma-aminobutyric acid receptor life cycle pathway;Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation;sumoylation as a mechanism to modulate ctbp-dependent gene responses;Coregulation of Androgen receptor activity;Tryptophan degradation;Regulation of Telomerase (Consensus)

Recessive Scores

• pRec: 0.472

Intolerance Scores

• rvis_EVS: -0.56
• rvis_percentile_EVS: 19.54

Haploinsufficiency Scores

• pHI: 0.408
• hipred: Y
• hipred_score: 0.816
• ghis: 0.665

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.881

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ube3a
• Phenotype: reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype; cellular phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: protein polyubiquitination;proteolysis;ubiquitin-dependent protein catabolic process;brain development;viral process;positive regulation of protein ubiquitination;response to progesterone;regulation of circadian rhythm;proteasome-mediated ubiquitin-dependent protein catabolic process;rhythmic process;progesterone receptor signaling pathway;protein autoubiquitination;protein K48-linked ubiquitination;regulation of ubiquitin-dependent protein catabolic process
• Cellular component: proteasome complex;nucleus;cytoplasm
• Molecular function: ubiquitin-protein transferase activity;protein binding;metal ion binding;ubiquitin protein ligase activity