Human Gene Module / Chromosome 15 / UBE3A

UBE3Aubiquitin protein ligase E3A

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
15 / 48
Rare Variants / Common Variants
42 / 2
Aliases
UBE3A, AS,  ANCR,  E6-AP,  HPVE6A,  EPVE6AP,  FLJ26981
Associated Syndromes
Angelman syndrome, ASD, Angelman syndrome
Chromosome Band
15q11.2
Associated Disorders
DD/NDD, ADHD, ID, EP, EPS, ASD
Relevance to Autism

Studies have found genetic association and rare variations in the UBE3A gene that are associated with autism. Association was found in families of the Collaborative Linkage Study of Autism (Nurmi et al., 2001), and rare variants were found in cases of European ancestry.

Molecular Function

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.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Fruit fly
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to UBE3A (48 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families Nurmi EL , et al. (2001) Yes -
2 Recent Recommendation Imprinting in neurons Kishino T (2006) No -
3 Recent Recommendation Ube3a expression is not altered in Mecp2 mutant mice Jordan C and Francke U (2006) No -
4 Recent Recommendation Gene symbol: UBE3A. Disease: Angelman syndrome Mueller OT and Coovadia A (2008) No -
5 Support Autism genome-wide copy number variation reveals ubiquitin and neuronal genes Glessner JT , et al. (2009) Yes -
6 Recent Recommendation Ube3a is required for experience-dependent maturation of the neocortex Yashiro K , et al. (2009) No -
7 Support Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders Schaaf CP , et al. (2011) Yes -
8 Support High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism Kelleher RJ 3rd , et al. (2012) Yes -
9 Recent Recommendation Impairment of TrkB-PSD-95 signaling in Angelman syndrome Cao C , et al. (2013) No -
10 Recent Recommendation E6AP/UBE3A ubiquitin ligase harbors two E2~ubiquitin binding sites Ronchi VP , et al. (2013) No -
11 Recent Recommendation Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc Khnle S , et al. (2013) No -
12 Support Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1 Carvill GL , et al. (2013) No ID, ASD, DD
13 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
14 Support Whole-genome sequencing of quartet families with autism spectrum disorder Yuen RK , et al. (2015) Yes -
15 Recent Recommendation A coding-independent function of an alternative Ube3a transcript during neuronal development Valluy J , et al. (2015) No -
16 Support 15q11.2 Duplication Encompassing Only the UBE3A Gene Is Associated with Developmental Delay and Neuropsychiatric Phenotypes Noor A , et al. (2015) No Neuropsychiatric phenotypes (anxiety, depression)
17 Recent Recommendation UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis Sun J , et al. (2015) No -
18 Recent Recommendation An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A Yi JJ , et al. (2015) No -
19 Recent Recommendation Angelman Syndrome Protein Ube3a Regulates Synaptic Growth and Endocytosis by Inhibiting BMP Signaling in Drosophila Li W , et al. (2016) No -
20 Support High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing Martnez F , et al. (2016) No ID
21 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No DD, epilepsy/seizures
22 Support Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes Parrini E , et al. (2016) No Angelman syndrome
23 Support The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/?-catenin pathway by inhibiting the proteasome Yi JJ , et al. (2017) No -
24 Support Expanding the genetic heterogeneity of intellectual disability Anazi S , et al. (2017) No -
25 Support Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice Tumien B , et al. (2017) No ADHD
26 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes Xiong J , et al. (2019) Yes ID
27 Support Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression Yin J et al. (2020) Yes Developmental regression, ID, epilepsy/seizures
28 Support A novel UBE3A sequence variant identified in eight related individuals with neurodevelopmental delay, results in a phenotype which does not match the clinical criteria of Angelman syndrome Geerts-Haages A et al. (2020) No Epilepsy/seizures
29 Support - Rodin RE et al. (2021) Yes -
30 Support - Taşkıran EZ et al. (2021) No Epilepsy/seizures
31 Support - Kritioti E et al. (2021) No -
32 Support - Berg EL et al. (2021) No -
33 Support - Pode-Shakked B et al. (2021) No -
34 Support - Chen S et al. (2021) Yes DD, ID, epilepsy/seizures
35 Recent Recommendation - Weston KP et al. (2021) No ASD, ADHD
36 Support - Álvarez-Mora MI et al. (2022) No -
37 Support - Zhao X et al. (2022) No -
38 Support - Chuan Z et al. (2022) No DD
39 Support - Lee D et al. (2023) No -
40 Support - Xing L et al. (2023) Yes -
41 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
42 Support - Ko YJ et al. (2023) No -
43 Support - Kotaro Furusawa et al. (2023) Yes -
44 Support - Magdalena Badura-Stronka et al. (2024) No ID
45 Support - Zachary Gardner et al. (2024) Yes -
46 Support - Caterina Montani et al. (2024) Yes -
47 Support - Axel Schmidt et al. (2024) No -
48 Highly Cited UBE3A/E6-AP mutations cause Angelman syndrome Kishino T , et al. (1997) No -
Rare Variants   (42)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1437C>A p.Tyr479Ter stop_gained De novo - - 34800434 Chen S et al. (2021)
c.-284del - frameshift_variant - - Multiplex 28940097 Anazi S , et al. (2017)
c.1437C>A p.Tyr479Ter stop_gained De novo - - 31031587 Xiong J , et al. (2019)
c.408T>C p.Ile136= missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.2281G>A p.Gly761Arg missense_variant De novo - - 29286531 Tumien B , et al. (2017)
c.1546C>T p.Arg516Trp missense_variant Unknown - - 34815418 Weston KP et al. (2021)
c.2359A>G p.Thr787Ala missense_variant Unknown - - 34815418 Weston KP et al. (2021)
c.2110C>G p.Pro704Ala missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
- - copy_number_loss De novo - Simplex 38328757 Magdalena Badura-Stronka et al. (2024)
c.2439C>G p.Asp813Glu missense_variant Unknown - Unknown 32722525 Yin J et al. (2020)
c.2549C>T p.Pro850Leu missense_variant De novo - Simplex 37645600 Ko YJ et al. (2023)
c.2410C>T p.Gln804Ter stop_gained De novo - Simplex 34324503 Kritioti E et al. (2021)
c.1973A>G p.Gln658Arg missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
- - copy_number_gain Familial Maternal Multi-generational 25884337 Noor A , et al. (2015)
c.1269C>T p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.520A>G p.Thr174Ala missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.1453A>G p.Thr485Ala missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.333C>G p.Asn111Lys missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.1561G>A p.Ala521Thr missense_variant Familial Maternal - 34815418 Weston KP et al. (2021)
c.2609G>A p.Gly870Asp missense_variant De novo - Multiplex 27620904 Martnez F , et al. (2016)
c.1845dup p.Gly616TrpfsTer11 frameshift_variant De novo - Simplex 37645600 Ko YJ et al. (2023)
c.2586_2587del p.Leu862PhefsTer21 frameshift_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.2576_2579del p.Lys859ArgfsTer4 frameshift_variant De novo - - 31031587 Xiong J , et al. (2019)
c.2263G>A p.Gly755Ser missense_variant Unknown Not maternal - 34815418 Weston KP et al. (2021)
c.312_315del p.Asn105ThrfsTer6 frameshift_variant De novo - - 27864847 Parrini E , et al. (2016)
c.1682G>A p.Gly561Glu missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.328G>A p.Glu110Lys missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.2402T>A p.Leu801His missense_variant Familial Maternal Simplex 34815418 Weston KP et al. (2021)
c.2359A>G p.Thr787Ala missense_variant Familial Maternal Multiplex 34815418 Weston KP et al. (2021)
c.2516_2519del p.Thr839IlefsTer24 frameshift_variant Familial Maternal - 34800434 Chen S et al. (2021)
c.1585C>T p.Arg529Cys missense_variant Familial Maternal Multiplex 23708187 Carvill GL , et al. (2013)
c.2572_2573insCTTA p.Leu858ProfsTer3 frameshift_variant De novo - - 27848944 Trujillano D , et al. (2016)
c.2185_2187del p.Gln729del inframe_deletion Familial Maternal Multiplex 34815418 Weston KP et al. (2021)
c.2029G>C p.Gly677Arg missense_variant Familial Maternal Extended multiplex 35225435 Zhao X et al. (2022)
c.1798del p.Trp600GlyfsTer15 frameshift_variant Familial Maternal Multiplex 25621899 Yuen RK , et al. (2015)
c.386_390del p.Thr129ArgfsTer5 frameshift_variant De novo - Simplex 33739554 Taşkıran EZ et al. (2021)
c.2019del p.Asp674MetfsTer3 frameshift_variant Familial Maternal - 35183220 Álvarez-Mora MI et al. (2022)
c.1978_1979insCAGAGTTTAAAAG p.Gln660ProfsTer14 frameshift_variant De novo - - 29286531 Tumien B , et al. (2017)
c.573_581del p.Asp191_Lys193del inframe_deletion Familial Paternal Simplex 21624971 Schaaf CP , et al. (2011)
c.1018_1020del p.Phe340del inframe_deletion Familial Maternal Extended multiplex 32889787 Geerts-Haages A et al. (2020)
c.601G>A p.Ala201Thr missense_variant Familial (5 cases), Unknown (5 cases) Maternal (3 cases); paternal (2 cases) Simplex 21624971 Schaaf CP , et al. (2011)
ENSG00000114062:ENST00000397954:exon10:c.C2429T:p.T810M,ENSG00000114062:ENST00000428984:exon11:c.C23 - missense_variant De novo - - 33432195 Rodin RE et al. (2021)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - microsatellite - - - 11543639 Nurmi EL , et al. (2001)
- - copy_number_gain - - - 19404257 Glessner JT , et al. (2009)
SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2021
1
icon
1

Score remained at 1

Description

UBE3A is present in common 15q11-13 duplications which involves autism (Glessner et al., 2009; Bucan et al., 2009 and many other references reporting duplication). Angelman syndrome results predominantly either from de novo 15q11-q13 deletions on the maternal chromosome or mutations in UBE3A. A number of other rare variants which have been associated with this gene and/or association studies without sufficient statistical significance to warrant elevating the gene. Schaaf et al., 2011 found novel coding variants but was not statistically strong in a case-control study. Kim et al., 2008 failed to find association in TdT tests. Nurmi et al., reported a preliminary study of association (2003). Veenstra-VanderWeele reported rare variants with resequencing in 1999, but with no case-control sequencing. A de novo missense variant in UBE3A (p.Thr485Ala) that was identified in a male ASD proband from the Simons Simplex Collection in PMID 25363768 was demonstrated in PMID 26255772 to abolish a phosphorylation site involved in regulating UBE3A activity. As a result of this variant, mutant UBE3A showed enhanced UBE3A activity in vitro and enhanced substrate turnover, which in turn caused excessive dendritic spine development in vivo. Increased UBE3A gene dosage in mice resulted in defective social interaction, impaired communication, and increased repetitive stereotypic behavior in PMID 21974935.

Reports Added
[Diagnostic yield of whole-exome sequencing in non-syndromic intellectual disability2021]
1/1/2021
1
icon
1

Score remained at 1

Description

UBE3A is present in common 15q11-13 duplications which involves autism (Glessner et al., 2009; Bucan et al., 2009 and many other references reporting duplication). Angelman syndrome results predominantly either from de novo 15q11-q13 deletions on the maternal chromosome or mutations in UBE3A. A number of other rare variants which have been associated with this gene and/or association studies without sufficient statistical significance to warrant elevating the gene. Schaaf et al., 2011 found novel coding variants but was not statistically strong in a case-control study. Kim et al., 2008 failed to find association in TdT tests. Nurmi et al., reported a preliminary study of association (2003). Veenstra-VanderWeele reported rare variants with resequencing in 1999, but with no case-control sequencing. A de novo missense variant in UBE3A (p.Thr485Ala) that was identified in a male ASD proband from the Simons Simplex Collection in PMID 25363768 was demonstrated in PMID 26255772 to abolish a phosphorylation site involved in regulating UBE3A activity. As a result of this variant, mutant UBE3A showed enhanced UBE3A activity in vitro and enhanced substrate turnover, which in turn caused excessive dendritic spine development in vivo. Increased UBE3A gene dosage in mice resulted in defective social interaction, impaired communication, and increased repetitive stereotypic behavior in PMID 21974935.

Reports Added
[The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing2021]
10/1/2020
1
icon
1

Score remained at 1

Description

UBE3A is present in common 15q11-13 duplications which involves autism (Glessner et al., 2009; Bucan et al., 2009 and many other references reporting duplication). Angelman syndrome results predominantly either from de novo 15q11-q13 deletions on the maternal chromosome or mutations in UBE3A. A number of other rare variants which have been associated with this gene and/or association studies without sufficient statistical significance to warrant elevating the gene. Schaaf et al., 2011 found novel coding variants but was not statistically strong in a case-control study. Kim et al., 2008 failed to find association in TdT tests. Nurmi et al., reported a preliminary study of association (2003). Veenstra-VanderWeele reported rare variants with resequencing in 1999, but with no case-control sequencing. A de novo missense variant in UBE3A (p.Thr485Ala) that was identified in a male ASD proband from the Simons Simplex Collection in PMID 25363768 was demonstrated in PMID 26255772 to abolish a phosphorylation site involved in regulating UBE3A activity. As a result of this variant, mutant UBE3A showed enhanced UBE3A activity in vitro and enhanced substrate turnover, which in turn caused excessive dendritic spine development in vivo. Increased UBE3A gene dosage in mice resulted in defective social interaction, impaired communication, and increased repetitive stereotypic behavior in PMID 21974935.

Reports Added
[A novel UBE3A sequence variant identified in eight related individuals with neurodevelopmental delay, results in a phenotype which does not match the clinical criteria of Angelman syndrome2020]
7/1/2020
1
icon
1

Score remained at 1

Description

UBE3A is present in common 15q11-13 duplications which involves autism (Glessner et al., 2009; Bucan et al., 2009 and many other references reporting duplication). Angelman syndrome results predominantly either from de novo 15q11-q13 deletions on the maternal chromosome or mutations in UBE3A. A number of other rare variants which have been associated with this gene and/or association studies without sufficient statistical significance to warrant elevating the gene. Schaaf et al., 2011 found novel coding variants but was not statistically strong in a case-control study. Kim et al., 2008 failed to find association in TdT tests. Nurmi et al., reported a preliminary study of association (2003). Veenstra-VanderWeele reported rare variants with resequencing in 1999, but with no case-control sequencing. A de novo missense variant in UBE3A (p.Thr485Ala) that was identified in a male ASD proband from the Simons Simplex Collection in PMID 25363768 was demonstrated in PMID 26255772 to abolish a phosphorylation site involved in regulating UBE3A activity. As a result of this variant, mutant UBE3A showed enhanced UBE3A activity in vitro and enhanced substrate turnover, which in turn caused excessive dendritic spine development in vivo. Increased UBE3A gene dosage in mice resulted in defective social interaction, impaired communication, and increased repetitive stereotypic behavior in PMID 21974935.

Reports Added
[Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression2020]
10/1/2019
3S
icon
1

Decreased from 3S to 1

New Scoring Scheme
Description

UBE3A is present in common 15q11-13 duplications which involves autism (Glessner et al., 2009; Bucan et al., 2009 and many other references reporting duplication). Angelman syndrome results predominantly either from de novo 15q11-q13 deletions on the maternal chromosome or mutations in UBE3A. A number of other rare variants which have been associated with this gene and/or association studies without sufficient statistical significance to warrant elevating the gene. Schaaf et al., 2011 found novel coding variants but was not statistically strong in a case-control study. Kim et al., 2008 failed to find association in TdT tests. Nurmi et al., reported a preliminary study of association (2003). Veenstra-VanderWeele reported rare variants with resequencing in 1999, but with no case-control sequencing. A de novo missense variant in UBE3A (p.Thr485Ala) that was identified in a male ASD proband from the Simons Simplex Collection in PMID 25363768 was demonstrated in PMID 26255772 to abolish a phosphorylation site involved in regulating UBE3A activity. As a result of this variant, mutant UBE3A showed enhanced UBE3A activity in vitro and enhanced substrate turnover, which in turn caused excessive dendritic spine development in vivo. Increased UBE3A gene dosage in mice resulted in defective social interaction, impaired communication, and increased repetitive stereotypic behavior in PMID 21974935.

Reports Added
[New Scoring Scheme]
4/1/2019
3S
icon
3S

Decreased from 3S to 3S

Description

UBE3A is present in common 15q11-13 duplications which involves autism (Glessner et al., 2009; Bucan et al., 2009 and many other references reporting duplication). Angelman syndrome results predominantly either from de novo 15q11-q13 deletions on the maternal chromosome or mutations in UBE3A. A number of other rare variants which have been associated with this gene and/or association studies without sufficient statistical significance to warrant elevating the gene. Schaaf et al., 2011 found novel coding variants but was not statistically strong in a case-control study. Kim et al., 2008 failed to find association in TdT tests. Nurmi et al., reported a preliminary study of association (2003). Veenstra-VanderWeele reported rare variants with resequencing in 1999, but with no case-control sequencing. A de novo missense variant in UBE3A (p.Thr485Ala) that was identified in a male ASD proband from the Simons Simplex Collection in PMID 25363768 was demonstrated in PMID 26255772 to abolish a phosphorylation site involved in regulating UBE3A activity. As a result of this variant, mutant UBE3A showed enhanced UBE3A activity in vitro and enhanced substrate turnover, which in turn caused excessive dendritic spine development in vivo. Increased UBE3A gene dosage in mice resulted in defective social interaction, impaired communication, and increased repetitive stereotypic behavior in PMID 21974935.

Reports Added
[Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.2019]
10/1/2017
3S
icon
3S

Decreased from 3S to 3S

Description

UBE3A is present in common 15q11-13 duplications which involves autism (Glessner et al., 2009; Bucan et al., 2009 and many other references reporting duplication). Angelman syndrome results predominantly either from de novo 15q11-q13 deletions on the maternal chromosome or mutations in UBE3A. A number of other rare variants which have been associated with this gene and/or association studies without sufficient statistical significance to warrant elevating the gene. Schaaf et al., 2011 found novel coding variants but was not statistically strong in a case-control study. Kim et al., 2008 failed to find association in TdT tests. Nurmi et al., reported a preliminary study of association (2003). Veenstra-VanderWeele reported rare variants with resequencing in 1999, but with no case-control sequencing. A de novo missense variant in UBE3A (p.Thr485Ala) that was identified in a male ASD proband from the Simons Simplex Collection in PMID 25363768 was demonstrated in PMID 26255772 to abolish a phosphorylation site involved in regulating UBE3A activity. As a result of this variant, mutant UBE3A showed enhanced UBE3A activity in vitro and enhanced substrate turnover, which in turn caused excessive dendritic spine development in vivo. Increased UBE3A gene dosage in mice resulted in defective social interaction, impaired communication, and increased repetitive stereotypic behavior in PMID 21974935.

Reports Added
[Expanding the genetic heterogeneity of intellectual disability.2017]
4/1/2017
3S
icon
3S

Decreased from 3S to 3S

Description

UBE3A is present in common 15q11-13 duplications which involves autism (Glessner et al., 2009; Bucan et al., 2009 and many other references reporting duplication). Angelman syndrome results predominantly either from de novo 15q11-q13 deletions on the maternal chromosome or mutations in UBE3A. A number of other rare variants which have been associated with this gene and/or association studies without sufficient statistical significance to warrant elevating the gene. Schaaf et al., 2011 found novel coding variants but was not statistically strong in a case-control study. Kim et al., 2008 failed to find association in TdT tests. Nurmi et al., reported a preliminary study of association (2003). Veenstra-VanderWeele reported rare variants with resequencing in 1999, but with no case-control sequencing. A de novo missense variant in UBE3A (p.Thr485Ala) that was identified in a male ASD proband from the Simons Simplex Collection in PMID 25363768 was demonstrated in PMID 26255772 to abolish a phosphorylation site involved in regulating UBE3A activity. As a result of this variant, mutant UBE3A showed enhanced UBE3A activity in vitro and enhanced substrate turnover, which in turn caused excessive dendritic spine development in vivo. Increased UBE3A gene dosage in mice resulted in defective social interaction, impaired communication, and increased repetitive stereotypic behavior in PMID 21974935.

Reports Added
[Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families.2001] [Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.2009] [Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.2012] [UBE3A/E6-AP mutations cause Angelman syndrome.1997] [Imprinting in neurons.2006] [Ube3a expression is not altered in Mecp2 mutant mice.2006] [Gene symbol: UBE3A. Disease: Angelman syndrome.2008] [Ube3a is required for experience-dependent maturation of the neocortex.2009] [Impairment of TrkB-PSD-95 signaling in Angelman syndrome.2013] [E6AP/UBE3A ubiquitin ligase harbors two E2~ubiquitin binding sites.2013] [Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc.2013] [A coding-independent function of an alternative Ube3a transcript during neuronal development.2015] [15q11.2 Duplication Encompassing Only the UBE3A Gene Is Associated with Developmental Delay and Neuropsychiatric Phenotypes.2015] [UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A.2015] [Angelman Syndrome Protein Ube3a Regulates Synaptic Growth and Endocytosis by Inhibiting BMP Signaling in Drosophila.2016] [High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016] [The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/-catenin pathway by inhibiting the proteasome.2017]
1/1/2017
3S
icon
3S

Decreased from 3S to 3S

Description

UBE3A is present in common 15q11-13 duplications which involves autism (Glessner et al., 2009; Bucan et al., 2009 and many other references reporting duplication). Angelman syndrome results predominantly either from de novo 15q11-q13 deletions on the maternal chromosome or mutations in UBE3A. A number of other rare variants which have been associated with this gene and/or association studies without sufficient statistical significance to warrant elevating the gene. Schaaf et al., 2011 found novel coding variants but was not statistically strong in a case-control study. Kim et al., 2008 failed to find association in TdT tests. Nurmi et al., reported a preliminary study of association (2003). Veenstra-VanderWeele reported rare variants with resequencing in 1999, but with no case-control sequencing. A de novo missense variant in UBE3A (p.Thr485Ala) that was identified in a male ASD proband from the Simons Simplex Collection in PMID 25363768 was demonstrated in PMID 26255772 to abolish a phosphorylation site involved in regulating UBE3A activity. As a result of this variant, mutant UBE3A showed enhanced UBE3A activity in vitro and enhanced substrate turnover, which in turn caused excessive dendritic spine development in vivo. Increased UBE3A gene dosage in mice resulted in defective social interaction, impaired communication, and increased repetitive stereotypic behavior in PMID 21974935.

Reports Added
[Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016]
10/1/2016
3S
icon
3S

Decreased from 3S to 3S

Description

UBE3A is present in common 15q11-13 duplications which involves autism (Glessner et al., 2009; Bucan et al., 2009 and many other references reporting duplication). Angelman syndrome results predominantly either from de novo 15q11-q13 deletions on the maternal chromosome or mutations in UBE3A. A number of other rare variants which have been associated with this gene and/or association studies without sufficient statistical significance to warrant elevating the gene. Schaaf et al., 2011 found novel coding variants but was not statistically strong in a case-control study. Kim et al., 2008 failed to find association in TdT tests. Nurmi et al., reported a preliminary study of association (2003). Veenstra-VanderWeele reported rare variants with resequencing in 1999, but with no case-control sequencing. A de novo missense variant in UBE3A (p.Thr485Ala) that was identified in a male ASD proband from the Simons Simplex Collection in PMID 25363768 was demonstrated in PMID 26255772 to abolish a phosphorylation site involved in regulating UBE3A activity. As a result of this variant, mutant UBE3A showed enhanced UBE3A activity in vitro and enhanced substrate turnover, which in turn caused excessive dendritic spine development in vivo. Increased UBE3A gene dosage in mice resulted in defective social interaction, impaired communication, and increased repetitive stereotypic behavior in PMID 21974935.

Reports Added
[High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
4/1/2016
3S
icon
3S

Decreased from 3S to 3S

Description

UBE3A is present in common 15q11-13 duplications which involves autism (Glessner et al., 2009; Bucan et al., 2009 and many other references reporting duplication). Angelman syndrome results predominantly either from de novo 15q11-q13 deletions on the maternal chromosome or mutations in UBE3A. A number of other rare variants which have been associated with this gene and/or association studies without sufficient statistical significance to warrant elevating the gene. Schaaf et al., 2011 found novel coding variants but was not statistically strong in a case-control study. Kim et al., 2008 failed to find association in TdT tests. Nurmi et al., reported a preliminary study of association (2003). Veenstra-VanderWeele reported rare variants with resequencing in 1999, but with no case-control sequencing. A de novo missense variant in UBE3A (p.Thr485Ala) that was identified in a male ASD proband from the Simons Simplex Collection in PMID 25363768 was demonstrated in PMID 26255772 to abolish a phosphorylation site involved in regulating UBE3A activity. As a result of this variant, mutant UBE3A showed enhanced UBE3A activity in vitro and enhanced substrate turnover, which in turn caused excessive dendritic spine development in vivo. Increased UBE3A gene dosage in mice resulted in defective social interaction, impaired communication, and increased repetitive stereotypic behavior in PMID 21974935.

Reports Added
[Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families.2001] [Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.2009] [Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.2012] [UBE3A/E6-AP mutations cause Angelman syndrome.1997] [Imprinting in neurons.2006] [Ube3a expression is not altered in Mecp2 mutant mice.2006] [Gene symbol: UBE3A. Disease: Angelman syndrome.2008] [Ube3a is required for experience-dependent maturation of the neocortex.2009] [Impairment of TrkB-PSD-95 signaling in Angelman syndrome.2013] [E6AP/UBE3A ubiquitin ligase harbors two E2~ubiquitin binding sites.2013] [Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc.2013] [A coding-independent function of an alternative Ube3a transcript during neuronal development.2015] [15q11.2 Duplication Encompassing Only the UBE3A Gene Is Associated with Developmental Delay and Neuropsychiatric Phenotypes.2015] [UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A.2015] [Angelman Syndrome Protein Ube3a Regulates Synaptic Growth and Endocytosis by Inhibiting BMP Signaling in Drosophila.2016]
7/1/2015
S
icon
3S

Increased from S to 3S

Description

UBE3A is present in common 15q11-13 duplications which involves autism (Glessner et al., 2009; Bucan et al., 2009 and many other references reporting duplication). Angelman syndrome results predominantly either from de novo 15q11-q13 deletions on the maternal chromosome or mutations in UBE3A. A number of other rare variants which have been associated with this gene and/or association studies without sufficient statistical significance to warrant elevating the gene. Schaaf et al., 2011 found novel coding variants but was not statistically strong in a case-control study. Kim et al., 2008 failed to find association in TdT tests. Nurmi et al., reported a preliminary study of association (2003). Veenstra-VanderWeele reported rare variants with resequencing in 1999, but with no case-control sequencing. A de novo missense variant in UBE3A (p.Thr485Ala) that was identified in a male ASD proband from the Simons Simplex Collection in PMID 25363768 was demonstrated in PMID 26255772 to abolish a phosphorylation site involved in regulating UBE3A activity. As a result of this variant, mutant UBE3A showed enhanced UBE3A activity in vitro and enhanced substrate turnover, which in turn caused excessive dendritic spine development in vivo. Increased UBE3A gene dosage in mice resulted in defective social interaction, impaired communication, and increased repetitive stereotypic behavior in PMID 21974935.

Reports Added
[Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families.2001] [Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.2009] [Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.2012] [UBE3A/E6-AP mutations cause Angelman syndrome.1997] [Imprinting in neurons.2006] [Ube3a expression is not altered in Mecp2 mutant mice.2006] [Gene symbol: UBE3A. Disease: Angelman syndrome.2008] [Ube3a is required for experience-dependent maturation of the neocortex.2009] [Impairment of TrkB-PSD-95 signaling in Angelman syndrome.2013] [E6AP/UBE3A ubiquitin ligase harbors two E2~ubiquitin binding sites.2013] [Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc.2013] [A coding-independent function of an alternative Ube3a transcript during neuronal development.2015] [15q11.2 Duplication Encompassing Only the UBE3A Gene Is Associated with Developmental Delay and Neuropsychiatric Phenotypes.2015] [UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A.2015]
4/1/2015
S
icon
S

Increased from S to S

Description

Present in common 15q11-13 duplication which involves autism (Glessner et al., 2009; Bucan et al., 2009 and many other references reporting duplication). A number of other rare variants which have been associated with this gene and/or association studies without sufficient statistical significance to warrant elevating the gene. Schaaf et al., 2011 find novel coding variants but not statistically strong in case-control study. Kim et al., 2008 fail to find association in TdT tests. Nurmi et al., report prelim study of association (2003). Veenstra-VanderWeele reports rare variants with resequencing in 1999. No case-control sequencing.

Reports Added
[A coding-independent function of an alternative Ube3a transcript during neuronal development.2015] [15q11.2 Duplication Encompassing Only the UBE3A Gene Is Associated with Developmental Delay and Neuropsychiatric Phenotypes.2015]
1/1/2015
S
icon
S

Increased from S to S

Description

Present in common 15q11-13 duplication which involves autism (Glessner et al., 2009; Bucan et al., 2009 and many other references reporting duplication). A number of other rare variants which have been associated with this gene and/or association studies without sufficient statistical significance to warrant elevating the gene. Schaaf et al., 2011 find novel coding variants but not statistically strong in case-control study. Kim et al., 2008 fail to find association in TdT tests. Nurmi et al., report prelim study of association (2003). Veenstra-VanderWeele reports rare variants with resequencing in 1999. No case-control sequencing.

Reports Added
[Whole-genome sequencing of quartet families with autism spectrum disorder.2015]
Krishnan Probability Score

Score 0.57047232918466

Ranking 917/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.9995762439583

Ranking 899/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.93793256990487

Ranking 13691/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score -0.10514181672056

Ranking 12541/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
CNVs associated with UBE3A(1 CNVs)
Sort By:
15q11.2 122 Deletion-Duplication 161  /  2259
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
AFG3L1P AFG3-like AAA ATPase 1, pseudogene Human Protein Binding 172
AHSP alpha hemoglobin stabilizing protein Human Protein Binding 51327 Q549J4
ANXA1 annexin A1 Human Protein Binding 301 P04083
Arc activity regulated cytoskeletal-associated protein Mouse Protein Binding 11838 Q9WV31
Arhgef15 Rho guanine nucleotide exchange factor (GEF) 15 Mouse Protein Binding 442801 Q5FWH6
ASAP3 ArfGAP with SH3 domain, ankyrin repeat and PH domain 3 Human Protein Binding 55616 Q8TDY4
BMAL1 Aryl hydrocarbon receptor nuclear translocator-like protein 1 Human Protein Binding 406 O00327
BPY2 basic charge, Y-linked, 2 Human Protein Binding 9083 O14599
CELA2B Chymotrypsin-like elastase family member 2B Human Protein Binding 51032 P08218
CG8209 Fruit Fly Protein Binding 38888 Q9VSC5
DERA deoxyribose-phosphate aldolase (putative) Human Protein Binding 51071 Q9Y315
ERCC6L2 excision repair cross-complementing rodent repair deficiency, complementation group 6-like 2 Human Protein Binding 375748 Q5T890
Kcnn2 potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2 Mouse Protein Binding 140492 P58390
KLHL38 kelch-like family member 38 Human Protein Binding 340359 Q2WGJ6
MAGEA8 melanoma antigen family A8 Human Protein Binding 4107 B2R9W4
miR-134 microRNA 134 Human RNA Binding 406924 N/A
PIPSL PIP5K1A and PSMD4-like, pseudogene Human Protein Binding 266971 A2A3N6
PSMB7 proteasome (prosome, macropain) subunit, beta type, 7 Human Protein Binding 5695 E9KL30
Rpn10 26S proteasome non-ATPase regulatory subunit 4 Fruit Fly Protein Binding 40388 P55035
SERHL2 Serine hydrolase-like protein 2 Human Protein Binding 253190 Q9H4I8
SHBG sex hormone-binding globulin Human Protein Binding 6462 P04278
TRPV5 Transient receptor potential cation channel subfamily V member 5 Human Protein Binding 56302 E9PBZ6
Uch-L5 Ubiquitin C-terminal hydrolase Fruit Fly Protein Binding 39102 Q9XZ61
Submit New Gene

Report an Error