UBE3A

protein-coding

ubiquitin protein ligase E3A, the group of HECT domain containing

Gene summary

This gene encodes an E3 ubiquitin-protein ligase, part of the ubiquitin protein degradation system. This imprinted gene is maternally expressed in brain and biallelically expressed in other tissues. Maternally inherited deletion of this gene causes Angelman Syndrome, characterized by severe motor and intellectual retardation, ataxia, hypotonia, epilepsy, absence of speech, and characteristic facies. The protein also interacts with the E6 protein of human papillomavirus types 16 and 18, resulting in ubiquitination and proteolysis of tumor protein p53. Alternative splicing of this gene results in three transcript variants encoding three isoforms with different N-termini. Additional transcript variants have been described, but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

Previous symbols:

EPVE6AP
HPVE6A

MANE transcript

NM_130839.5

Inheritance

ClinVar variants

P:281U:383B:216

Top phenotype

Angelman syndrome

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr15:25,333,728-25,439,051

External References & Databases

Ensembl (ENSG00000114062)

Transcript & Mutation Effects

hg38 • Region Span ~105.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Angelman syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007113

Submitter: ClinGen

Angelman syndrome (AS) is caused by loss-of-function of the maternally-inherited copy of UBE3A by a variety of genetic mechanisms. The paternal copy of the gene is imprinted in the brain, so variants on the paternal allele do not manifest as AS in the individual. Angelman syndrome is characterized by severe developmental delay and intellectual disability, speech impairment, gait ataxia, trembling of limbs, microcephaly, seizures, and happy demeanor. About 70% of AS is caused by microdeletions of 15q11-13, about 7% by uniparental disomy, 3% by imprinting center defects, 10% by variants in the UBE3A gene, and the remaining 10% are unknown (see Fang et al. 1999 for review of UBE3A variant spectrum). Variants can arise de novo or be inherited from the patient's mother. Mouse models with maternally-derived null alleles recapitulate many of the phenotypic features of AS, and unsilencing of paternal wild-type UBE3A expression in mice ameliorated many of the phenotypic defects seen in the mouse model (Jiang et al. 1998, Miura et al. 2002, Meng et al. 2013). In summary, the UBE3A gene is definitively associated with AS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. More information can be found at GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1144/).

Angelman syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007113

Submitter: PanelApp Australia

Angelman syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007113

Submitter: G2P

Angelman syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007113

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Angelman syndromeAD

Manifestation: Neurologic

Intervention: General

Rationale: 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

Refs: 8988171; 8988172; 9546330; 10196695; 11748306; 12210318; 15150776; 20034088; 20933619; 21072004; 21204213; 21362313; 21397058; 22065487

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UBE3A variants in ClinVar

19 Conditions Cataloged

Angelman syndromeTotal: 762

not providedTotal: 323

Inborn genetic diseasesTotal: 97

not specifiedTotal: 70

UBE3A-related disorderTotal: 25

Intellectual disabilityTotal: 10

See casesTotal: 4

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_130839.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			8 clinvar	185 clinvar	12 clinvar	205
missense	20 clinvar	43 clinvar	370 clinvar	13 clinvar	5 clinvar	451
nonsense	47 clinvar	10 clinvar				57
start loss						0
frameshift	118 clinvar	32 clinvar	2 clinvar			152
splice donor/acceptor (+/-2bp)	8 clinvar	3 clinvar	3 clinvar	1 clinvar		15
Total	193	88	383	199	17	880

Highest pathogenic variant AF is 0.000004957336

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 101 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_130839.5	RefSeq	NP_570854.1	11	MANE Select
ENST00000648336.2	Ensembl	ENSP00000497572.2	11	MANE Select
NM_000462.5	RefSeq	NP_000453.2	11	Standard
NM_001354505.1	RefSeq	NP_001341434.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

protein polyubiquitination
proteolysis
ubiquitin-dependent protein catabolic process
brain development
viral process

Molecular Function

ubiquitin-protein transferase activity
protein binding
metal ion binding
ubiquitin protein ligase activity

Cellular Component

proteasome complex
nucleus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000397954
Coding exons: 11
Length: 101748
Individuals with no LoFs: 125706
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125709
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.40	191	455	0.419	0.0000238	5818
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.0000089	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.472

Intolerance Scores

RVIS EVS: -0.56
RVIS percentile EVS: 19.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.881

Gene Damage Prediction

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