HUWE1

protein-coding

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

Gene summary

This gene encodes a protein containing a C-terminal HECT (E6AP type E3 ubiquitin protein ligase) domain that functions as an E3 ubiquitin ligase. The encoded protein is required for the ubiquitination and subsequent degradation of the anti-apoptotic protein Mcl1 (myeloid cell leukemia sequence 1 (BCL2-related)). This protein also ubiquitinates the p53 tumor suppressor, core histones, and DNA polymerase beta. Mutations in this gene are associated with Turner type X-linked syndromic cognitive disability. [provided by RefSeq, Aug 2013]

MANE transcript

NM_031407.7

Inheritance

XL, AD

ClinVar variants

P:95U:1490B:538

Top phenotype

Intellectual developmental disorder, X-linked syndromic, Turner type; Xp11.22 microduplication syndrome

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chrX:53,532,096-53,686,752

External References & Databases

Ensembl (ENSG00000086758)

Transcript & Mutation Effects

hg38 • Region Span ~154.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked, syndromic, Turner typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010407

Submitter: G2P

non-syndromic X-linked intellectual disabilityDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: ClinGen

*HUWE1* variants were first reported in relation to non-syndromic X-linked intellectual disability in 2007 (PMID:18047645). *HUWE1* encodes a protein that plays a role in anti-apoptotic protein Mcl1 ubiquitination and degradation. The phenotypes associated with variants in *HUWE1* include varying degrees of intellectual disability, dysmorphic facial features, macro- and microcephaly, and short stature. At least 8 unique variants (missense) reported in 18 probands from 9 publications (PMIDs:27130160, 27615324, 23721686, 26587761, 23092983, 18252232, 25652354, 24307393, 18047645) have been included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by experimental evidence including biochemical functional studies, animal models, rescue, and functional alteration of patient cells (PMIDs:28193319, 20007713, 20231446, 28445732, 18047645, 27130160). In summary, there is definitive evidence to support the gene-disease relationship between *HUWE1* and non-syndromic X-linked intellectual disability. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on October 20, 2017. As of June 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.

intellectual developmental disorder, X-linked, syndromic, Turner typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010407

Submitter: Illumina

intellectual developmental disorder, X-linked, syndromic, Turner typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010407

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, X-linked, syndromic, Turner typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010407

Submitter: Ambry Genetics

intellectual developmental disorder, X-linked, syndromic, Turner typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010407

Submitter: PanelApp Australia

syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Orphanet

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked syndromic, Turner type; Xp11.22 microduplication syndromeXL

Manifestation: Craniofacial; Genitourinary; 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

Comments: In Xp11.22 microduplication syndrome, the phenotype appears to be due to increased HUWE1 dosage

Refs: 25985138; 27130160; 27615324; 27884935; 29180823; 30797980

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HUWE1 variants in ClinVar

34 Conditions Cataloged

not providedTotal: 1636

Inborn genetic diseasesTotal: 317

Intellectual disability, X-linked syndromic, Turner typeTotal: 248

not specifiedTotal: 197

HUWE1-related disorderTotal: 134

Intellectual disabilityTotal: 20

Trigonocephaly-short stature-developmental delay syndromeTotal: 3

Neurodevelopmental abnormalityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_031407.7. 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			94 clinvar	324 clinvar	68 clinvar	486
missense	5 clinvar	83 clinvar	1241 clinvar	131 clinvar	14 clinvar	1474
nonsense		1 clinvar	51 clinvar			52
start loss						0
frameshift	1 clinvar		3 clinvar			4
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	101 clinvar	1 clinvar		107
Total	8	87	1490	456	82	2123

Highest pathogenic variant AF is 0.0000180065

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 67 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_031407.7	RefSeq	NP_113584.3	81	MANE Select
ENST00000262854.11	Ensembl	ENSP00000262854.6	81	MANE Select
NM_001441048.1	RefSeq	NP_001427977.1	81	Standard
NM_001441049.1	RefSeq	NP_001427978.1	81	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquitin mediated proteolysis - Homo sapiens (human)
Neutrophil degranulation
Innate Immune System
Immune System
Adaptive Immune System

Biological Process

protein polyubiquitination
base-excision repair
ubiquitin-dependent protein catabolic process
protein monoubiquitination
protein ubiquitination

Molecular Function

DNA binding
RNA binding
ubiquitin-protein transferase activity
protein binding
ubiquitin protein ligase activity

Cellular Component

extracellular region
nucleus
nucleoplasm
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000342160
Coding exons: 81
Length: 154617
Individuals with no LoFs: 125734
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125739
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	8.87	697	1.74e+3	0.401	0.000139	28585
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000077	0.000062	rare
Latino/Admixed American	0.000037	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000072	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0.00010	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.351

Intolerance Scores

LoFtool: 0.136
RVIS EVS: -3.36
RVIS percentile EVS: 0.4

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Indispensability pred.: E
Indispensability score: 0.713

Gene Damage Prediction

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