UBE4A

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

Basic information

Region (hg38): 11:118359600-118399211

Links

ENSG00000110344 ∙ NCBI:9354 ∙ OMIM:603753 ∙ HGNC:12499 ∙ Uniprot:Q14139 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal recessive non-syndromic intellectual disability (Supportive), mode of inheritance: AR
• multiple congenital anomalies/dysmorphic syndrome (Limited), mode of inheritance: AR
• neurodevelopmental disorder with hypotonia and gross motor and speech delay (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurodevelopmental disorder with hypotonia and gross motor and speech delay	AR	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	Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic	33420346

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the UBE4A gene.

• Neurodevelopmental disorder with hypotonia and gross motor and speech delay (2 variants)
• UBE4A-related disorder (1 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the UBE4A 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				3	1	4
missense			44	1		45
nonsense	2	1				3
start loss						0
frameshift	1	1				2
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding					1	1
Total	3	2	44	4	2

Variants in UBE4A

This is a list of pathogenic ClinVar variants found in the UBE4A region.

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

Position	Type	Phenotype	Significance	ClinVar
11-118365083-G-A			Uncertain significance (May 27, 2022)
11-118365090-C-A		Inborn genetic diseases	Uncertain significance (Feb 07, 2023)
11-118365139-G-C		Inborn genetic diseases	Likely benign (Apr 05, 2024)
11-118368652-A-C		Inborn genetic diseases	Uncertain significance (Apr 15, 2024)
11-118368669-G-A		Inborn genetic diseases	Uncertain significance (Jun 22, 2021)
11-118368726-C-T		Neurodevelopmental disorder with hypotonia and gross motor and speech delay	Likely pathogenic (Feb 02, 2023)
11-118368727-G-A		Inborn genetic diseases	Uncertain significance (Mar 18, 2024)
11-118369436-G-C		Inborn genetic diseases	Uncertain significance (Apr 22, 2022)
11-118369445-G-C			Likely benign (Jan 01, 2023)
11-118369462-G-A		Inborn genetic diseases • UBE4A-related disorder	Uncertain significance (Sep 28, 2021)
11-118369511-G-A		Neurodevelopmental disorder with hypotonia and gross motor and speech delay	Pathogenic (Mar 14, 2024)
11-118371581-C-T		Inborn genetic diseases	Uncertain significance (Feb 28, 2024)
11-118371624-T-A			Likely benign (Jan 01, 2023)
11-118372571-A-G		UBE4A-related disorder	Uncertain significance (Dec 15, 2023)
11-118372576-C-T		Neurodevelopmental disorder with hypotonia and gross motor and speech delay	Pathogenic (Mar 07, 2019)
11-118372585-C-T		Inborn genetic diseases	Uncertain significance (Aug 04, 2021)
11-118372659-G-C		UBE4A-related disorder	Uncertain significance (Dec 15, 2023)
11-118372686-C-G		Inborn genetic diseases	Likely benign (Oct 13, 2023)
11-118373103-G-C		Inborn genetic diseases	Uncertain significance (Jul 12, 2022)
11-118373197-G-C		Inborn genetic diseases	Uncertain significance (Jul 13, 2022)
11-118373250-A-G		Inborn genetic diseases	Uncertain significance (Mar 20, 2023)
11-118373253-C-A		Inborn genetic diseases	Uncertain significance (Nov 18, 2022)
11-118373282-G-A		Inborn genetic diseases	Uncertain significance (Aug 02, 2022)
11-118373524-C-G		not specified	Uncertain significance (May 06, 2024)
11-118373558-TG-T		UBE4A-related disorder	Pathogenic (Jan 03, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
UBE4A	protein_coding	protein_coding	ENST00000431736	19	39627

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.109	0.891	125727	0	17	125744	0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.21	436	587	0.743	0.0000312	7149
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000178	0.000178
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000937	0.0000924
European (Non-Finnish)	0.0000706	0.0000703
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

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}.
• Pathway: 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;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation (Consensus)

Recessive Scores

• pRec: 0.0990

Intolerance Scores

• loftool: 0.600
• rvis_EVS: -1.09
• rvis_percentile_EVS: 7.15

Haploinsufficiency Scores

• pHI: 0.206
• hipred: Y
• hipred_score: 0.639
• ghis: 0.531

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.869

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ube4a

Gene ontology

• Biological process: protein polyubiquitination;ubiquitin-dependent protein catabolic process;ubiquitin-dependent ERAD pathway
• Cellular component: ubiquitin ligase complex;nucleus;cytoplasm
• Molecular function: protein binding;ubiquitin-ubiquitin ligase activity