UBE4A

protein-coding

ubiquitination factor E4A, the group of U-box domain containing|Armadillo like helical domain containing

Gene summary

This gene encodes a member of the U-box ubiquitin ligase family. The encoded protein is involved in multiubiquitin chain assembly and plays a critical role in chromosome condensation and separation through the polyubiquitination of securin. Autoantibodies against the encoded protein may be markers for scleroderma and Crohn's disease. A pseudogene of this gene is located on the long arm of chromosome 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2011]

MANE transcript

NM_001204077.2

Inheritance

ClinVar variants

P:11U:138B:15

Top phenotype

Neurodevelopmental disorder with hypotonia and gross motor and speech delay

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr11:118,359,600-118,399,211

External References & Databases

Ensembl (ENSG00000110344)

Transcript & Mutation Effects

hg38 • Region Span ~39.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

neurodevelopmental disorder with hypotonia and gross motor and speech delaySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859207

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with hypotonia and gross motor and speech delaySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859207

Submitter: PanelApp Australia

neurodevelopmental disorder with hypotonia and gross motor and speech delaySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859207

Submitter: G2P

multiple congenital anomalies/dysmorphic syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019042

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with hypotonia and gross motor and speech delayAR

Manifestation: Craniofacial; Musculoskeletal; 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: 33420346

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UBE4A variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 119

not providedTotal: 25

Neurodevelopmental disorder with hypotonia and gross motor and speech delayTotal: 7

not specifiedTotal: 5

UBE4A-related disorderTotal: 5

Neurodevelopmental disorderTotal: 1

UBE4A-related neurodevelopmental disorderTotal: 1

Retinitis pigmentosa 11Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001204077.2. 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				10 clinvar	1 clinvar	11
missense			132 clinvar	4 clinvar		136
nonsense	2 clinvar	3 clinvar	2 clinvar			7
start loss			1 clinvar			1
frameshift	1 clinvar	4 clinvar				5
splice donor/acceptor (+/-2bp)		1 clinvar	3 clinvar			4
Total	3	8	138	14	1	164

Highest pathogenic variant AF is 0.000004788394

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001204077.2	RefSeq	NP_001191006.1	19	MANE Select
ENST00000252108.8	Ensembl	ENSP00000252108.4	19	MANE Select
NM_004788.4	RefSeq	NP_004779.2	19	Standard
ENST00000431736.6	Ensembl	ENSP00000387362.2	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquitin mediated proteolysis - Homo sapiens (human)
miR-targeted genes in epithelium - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase
Immune System

Biological Process

protein polyubiquitination
ubiquitin-dependent protein catabolic process
ubiquitin-dependent ERAD pathway

Molecular Function

protein binding
ubiquitin-ubiquitin ligase activity

Cellular Component

ubiquitin ligase complex
nucleus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000431736
Coding exons: 19
Length: 39627
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125744
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.21	436	587	0.743	0.0000312	7149
Missense (PolyPhen)		90	183.05	0.49168		2289
Synonymous	1.35	180	205	0.880	0.00000984	1993
Loss of Function	5.11	13	53.3	0.244	0.00000300	601

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000094	0.000092	rare
European (Non-Finnish)	0.000071	0.000070	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ubiquitin-protein ligase that probably functions as an E3 ligase in conjunction with specific E1 and E2 ligases. May also function as an E4 ligase mediating the assembly of polyubiquitin chains on substrates ubiquitinated by another E3 ubiquitin ligase. Mediates 'Lys-48'-linked polyubiquitination of substrates. {ECO:0000250|UniProtKB:E9Q735, ECO:0000250|UniProtKB:P54860}.;

Recessive Scores

pRec: 0.0990

Intolerance Scores

LoFtool: 0.600
RVIS EVS: -1.09
RVIS percentile EVS: 7.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.869

Gene Damage Prediction

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