UBE3B

protein-coding

ubiquitin protein ligase E3B, the group of HECT domain containing

Gene summary

The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin-protein ligases. This gene encodes a member of the E3 ubiquitin-conjugating enzyme family which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme and transfers the ubiquitin to the targeted substrates. A HECT (homology to E6-AP C-terminus) domain in the C-terminus of the longer isoform of this protein is the catalytic site of ubiquitin transfer and forms a complex with E2 conjugases. Shorter isoforms of this protein which lack the C-terminal HECT domain are therefore unlikely to bind E2 enzymes. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2012]

MANE transcript

NM_130466.4

Inheritance

ClinVar variants

P:74U:225B:152

Top phenotype

Kaufman oculocerebrofacial syndrome (Blepharophimosis-ptosis-intellectual disability syndrome)

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr12:109,477,402-109,536,705

External References & Databases

Ensembl (ENSG00000151148)

Transcript & Mutation Effects

hg38 • Region Span ~59.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

oculocerebrofacial syndrome, Kaufman typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009485

Submitter: ClinGen

The UBE3B gene is located on chromosome 12 at 12q24.11 and encodes ubiquitin protein ligase E3B. The UBE3B gene product plays a role in protein degradation by the ubiquitin proteasome system, which helps to regulate protein levels and remove damaged or abnormal proteins. UBE3B was first reported in relation to autosomal recessive Kaufman oculocerebrofacial syndrome in 2012 (Basel-Vanagaite et al., PMID 23200864). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included twelve unique variants (3 missense, 1 start-lost, 2 splice, 4 stop-gained, 2 frameshift) reported in ten unrelated probands in four publications (Basel-Vanagaite et al., 2012 PMID 23200864; Flex et al., 2013 PMID 23687348; Basel-Vanagaite et al., 2014 PMID 24615390; Pedurupillay et al., 2015 PMID 25691420). The missense variants were located in the functionally important HECT domain, but the functional consequence of these variants were not demonstrated experimentally. In one case, experimental studies suggested a mutant transcript escaped from nonsense-mediated decay. Variants in this gene segregated with disease in three additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by a shared biochemical function (ubiquitin-proteasome system) with at least one other gene associated with an intellectual disability syndrome (UBE3A:Angelman syndrome), developmental expression in the central nervous system and craniofacial structures consistent with the disease, and a homozygous null mouse model that recapitulates diverse clinical features observed in human patients (Basel-Vanagaite et al., 2012 PMID 23200864). In summary, UBE3B is definitively associated with autosomal recessive Kaufman oculocerebrofacial syndrome. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 6Jan2021 (SOP Version 8).

oculocerebrofacial syndrome, Kaufman typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009485

Submitter: G2P

oculocerebrofacial syndrome, Kaufman typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009485

Submitter: Orphanet

oculocerebrofacial syndrome, Kaufman typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009485

Submitter: Labcorp Genetics (formerly Invitae)

oculocerebrofacial syndrome, Kaufman typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009485

Submitter: Illumina

The UBE3B gene is located on chromosome 12 at 12q24.11 and encodes ubiquitin protein ligase E3B. The UBE3B gene product plays a role in protein degradation by the ubiquitin proteasome system, which helps to regulate protein levels and remove damaged or abnormal proteins. UBE3A was first reported in relation to autosomal recessive Kaufman oculocerebrofacial syndrome in 2012 (23200864: Basel-Vanagaite et al. 2012). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included eight variants (one missense, one start-lost, two splice-site, two stop-gained, and two frameshift) reported in six unrelated probands in three publications (23200864: Basel-Vanagaite et al. 2012; 23687348: Flex et al. 2013; 25691420: Pedurupillay et al. 2015). Variants in this gene segregated with disease in two additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by a shared biochemical function (ubiquitin-proteasome system) with at least one other gene associated with an intellectual disability syndrome (UBE3A:Angelman syndrome), expression in the central nervous system and craniofacial structures consistent with the disease, and a homozygous null mouse model that recapitulates diverse clinical features observed in human patients (23200864: Basel-Vanagaite et al. 2012). In summary, UBE3B is definitively associated with autosomal recessive Kaufman oculocerebrofacial syndrome. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

oculocerebrofacial syndrome, Kaufman typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009485

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Kaufman oculocerebrofacial syndrome (Blepharophimosis-ptosis-intellectual disability syndrome)AR

Manifestation: Craniofacial; Neurologic; Ophthalmologic

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: 23200864

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UBE3B variants in ClinVar

8 Conditions Cataloged

not providedTotal: 402

Inborn genetic diseasesTotal: 152

Oculocerebrofacial syndrome, Kaufman typeTotal: 55

UBE3B-related disorderTotal: 8

not specifiedTotal: 6

Intellectual disabilityTotal: 2

Blepharophimosis - intellectual disability syndromeTotal: 1

Optic nerve hypoplasiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_130466.4. 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		1 clinvar		127 clinvar	14 clinvar	142
missense	3 clinvar	4 clinvar	216 clinvar	10 clinvar	1 clinvar	234
nonsense	13 clinvar	5 clinvar				18
start loss		1 clinvar	1 clinvar			2
frameshift	18 clinvar	8 clinvar	1 clinvar			27
splice donor/acceptor (+/-2bp)	11 clinvar	10 clinvar	7 clinvar			28
Total	45	29	225	137	15	451

Highest pathogenic variant AF is 0.00005609515

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 63 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_130466.4	RefSeq	NP_569733.2	26	MANE Select
ENST00000342494.8	Ensembl	ENSP00000340596.3	26	MANE Select
NM_001270449.2	RefSeq	NP_001257378.1	7	Standard
NM_001270450.2	RefSeq	NP_001257379.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquitin mediated proteolysis - Homo sapiens (human)
Immune System
Adaptive Immune System
Antigen processing: Ubiquitination & Proteasome degradation
Class I MHC mediated antigen processing & presentation

Biological Process

protein polyubiquitination
ubiquitin-dependent protein catabolic process

Molecular Function

ubiquitin conjugating enzyme activity

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000342494
Coding exons: 26
Length: 59301
Individuals with no LoFs: 125673
Homozygous LoFs: 0
Heterozygous LoFs: 75
Defined: 125748
p: 0.000298

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.36	539	635	0.848	0.0000392	6997
Missense (PolyPhen)		130	186.44	0.69726		2048
Synonymous	0.861	232	249	0.931	0.0000153	2101
Loss of Function	4.47	24	62.0	0.387	0.00000352	661

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00041	0.00040	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00033	0.00033	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00033	0.00033	rare
South Asian	0.00016	0.00016	rare
Other	0.00016	0.00016	rare

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 then directly transfers the ubiquitin to targeted substrates. {ECO:0000250}.;

Recessive Scores

pRec: 0.0934

Intolerance Scores

LoFtool: 0.874
RVIS EVS: -2.23
RVIS percentile EVS: 1.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.531

Gene Damage Prediction

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