HUWE1

HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1, the group of Armadillo like helical domain containing|MicroRNA protein coding host genes|HECT domain containing

Basic information

Region (hg38): X:53532096-53686752

Links

ENSG00000086758 ∙ NCBI:10075 ∙ OMIM:300697 ∙ HGNC:30892 ∙ Uniprot:Q7Z6Z7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intellectual disability, X-linked syndromic, Turner type (Definitive), mode of inheritance: XL
• syndromic intellectual disability (Supportive), mode of inheritance: AD
• intellectual disability, X-linked syndromic, Turner type (Definitive), mode of inheritance: XL
• intellectual disability, X-linked syndromic, Turner type (Strong), mode of inheritance: XL
• intellectual disability, X-linked syndromic, Turner type (Definitive), mode of inheritance: XL
• non-syndromic X-linked intellectual disability (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, X-linked syndromic, Turner type; Xp11.22 microduplication syndrome	XL	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; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic	25985138; 27130160; 27615324; 27884935; 29180823; 30797980
In Xp11.22 microduplication syndrome, the phenotype appears to be due to increased HUWE1 dosage

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HUWE1 gene.

• not_provided (1467 variants)
• Inborn_genetic_diseases (290 variants)
• Intellectual_disability,_X-linked_syndromic,_Turner_type (224 variants)
• not_specified (97 variants)
• HUWE1-related_disorder (94 variants)
• Intellectual_disability (20 variants)
• Trigonocephaly-short_stature-developmental_delay_syndrome (4 variants)
• Neurodevelopmental_abnormality (2 variants)
• Global_developmental_delay (2 variants)
• Incidental_Discovery (1 variants)
• Ventricular_septal_defect (1 variants)
• Autism_spectrum_disorder (1 variants)
• Excessive_wrinkled_skin (1 variants)
• Intellectual_disability-hypotonic_facies_syndrome,_X-linked,_1 (1 variants)
• Rare_genetic_intellectual_disability (1 variants)
• Genetic_developmental_and_epileptic_encephalopathy (1 variants)
• X-linked_intellectual_disability (1 variants)
• Male_infertility_with_azoospermia_or_oligozoospermia_due_to_single_gene_mutation (1 variants)
• Abnormal_corpus_callosum_morphology (1 variants)
• Visual_impairment (1 variants)
• Blepharophimosis (1 variants)
• Neurodevelopmental_delay (1 variants)
• Hypothyroidism (1 variants)
• HUWE1-related_neurodevelopmental_disorder (1 variants)
• See_cases (1 variants)
• Severe_global_developmental_delay (1 variants)
• Non-syndromic_intellectual_disability (1 variants)
• Intellectual_disability,_X-linked_99 (1 variants)
• Abnormal_facial_shape (1 variants)
• Non-syndromic_X-linked_intellectual_disability (1 variants)
• Atrial_septal_defect (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HUWE1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000031407.7. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			93	254	82	429
missense	6	70	1114	114	15	1319
nonsense		1	50			51
start loss						0
frameshift	1		2			3
splice donor/acceptor (+/-2bp)	2	3	101	1		107
Total	9	74	1360	369	97

Highest pathogenic variant AF is 0.0000180065

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HUWE1	protein_coding	protein_coding	ENST00000342160	81	154617

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		125734	0	5	125739	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	8.87	697	1.74e+3	0.401	0.000139	28585
Missense in Polyphen		94	375.65	0.25023		6189
Synonymous	0.684	617	639	0.966	0.0000483	8866
Loss of Function	11.2	4	153	0.0261	0.0000125	2413

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000114	0.0000981
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000722	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.0000722	0.0000544
South Asian	0.000105	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins. Regulates apoptosis by catalyzing the polyubiquitination and degradation of MCL1. Mediates monoubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair. Also ubiquitinates the p53/TP53 tumor suppressor and core histones including H1, H2A, H2B, H3 and H4. Binds to an upstream initiator-like sequence in the preprodynorphin gene. Regulates neural differentiation and proliferation by catalyzing the polyubiquitination and degradation of MYCN. May regulate abundance of CDC6 after DNA damage by polyubiquitinating and targeting CDC6 to degradation. Mediates polyubiquitination of isoform 2 of PA2G4. {ECO:0000269|PubMed:15567145, ECO:0000269|PubMed:15767685, ECO:0000269|PubMed:15989956, ECO:0000269|PubMed:15989957, ECO:0000269|PubMed:17567951, ECO:0000269|PubMed:18488021, ECO:0000269|PubMed:19037095, ECO:0000269|PubMed:19713937}.
• Disease: DISEASE: Mental retardation, X-linked, syndromic, Turner type (MRXST) [MIM:300706]: A syndrome characterized by the association of mental retardation with macrocephaly and variable contractures. {ECO:0000269|PubMed:18252223}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mental retardation, X-linked 17 (MRX17) [MIM:300705]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non- syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. {ECO:0000269|PubMed:18252223}. Note=The gene represented in this entry is involved in disease pathogenesis. A chromosomal microduplication involving HSD17B10 and HUWE1 has been found in patients with mental retardation.
• Pathway: Ubiquitin mediated proteolysis - Homo sapiens (human);Neutrophil degranulation;Innate Immune System;Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation;EGFR1;Validated targets of C-MYC transcriptional activation;p53 pathway (Consensus)

Recessive Scores

• pRec: 0.351

Intolerance Scores

• loftool: 0.136
• rvis_EVS: -3.36
• rvis_percentile_EVS: 0.4

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.713

Gene Damage Prediction

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

Gene ontology

• Biological process: protein polyubiquitination;base-excision repair;ubiquitin-dependent protein catabolic process;protein monoubiquitination;protein ubiquitination;histone ubiquitination;cell differentiation;neutrophil degranulation;positive regulation of protein targeting to mitochondrion
• Cellular component: extracellular region;nucleus;nucleoplasm;cytoplasm;cytosol;membrane;secretory granule lumen;extracellular exosome;ficolin-1-rich granule lumen
• Molecular function: DNA binding;RNA binding;ubiquitin-protein transferase activity;protein binding;ubiquitin protein ligase activity