HACE1

HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1, the group of HECT domain containing|Ankyrin repeat domain containing

Basic information

Region (hg38): 6:104728094-104859919

Links

ENSG00000085382 ∙ NCBI:57531 ∙ OMIM:610876 ∙ HGNC:21033 ∙ Uniprot:Q8IYU2 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• spastic paraplegia-severe developmental delay-epilepsy syndrome (Strong), mode of inheritance: AR
• spastic paraplegia-severe developmental delay-epilepsy syndrome (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spastic paraplegia and psychomotor retardation with or without seizures	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; Neurologic	26424145; 26437029

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HACE1 gene.

• Spastic paraplegia-severe developmental delay-epilepsy syndrome (9 variants)
• not provided (3 variants)
• Generalized hypotonia;Global developmental delay;Seizure (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HACE1 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			2	58	6	66
missense	1	1	65		1	68
nonsense	8	2				10
start loss						0
frameshift	1	2				3
inframe indel			2			2
splice donor/acceptor (+/-2bp)		3				3
splice region		1	6	10	6	23
non coding			2	42	5	49
Total	10	8	71	100	12

Highest pathogenic variant AF is 0.0000132

Variants in HACE1

This is a list of pathogenic ClinVar variants found in the HACE1 region.

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

Position	Type	Phenotype	Significance	ClinVar
6-104729694-G-A			Uncertain significance (Aug 10, 2023)
6-104729709-G-C			Uncertain significance (Jul 22, 2022)
6-104729769-A-G			Likely benign (Jul 14, 2023)
6-104729779-T-A			Likely benign (Apr 08, 2022)
6-104730295-C-A		HACE1-related disorder	Likely benign (Apr 28, 2022)
6-104730297-A-C			Uncertain significance (Aug 07, 2019)
6-104730325-G-T		Inborn genetic diseases	Uncertain significance (Jan 31, 2022)
6-104730338-T-C			Likely benign (Jun 20, 2023)
6-104730350-G-A			Benign (Jan 03, 2018)
6-104730377-A-AC			Conflicting classifications of pathogenicity (Mar 20, 2023)
6-104730404-T-C			Likely benign (Mar 15, 2021)
6-104744140-A-T			Benign (Jan 16, 2024)
6-104744141-T-C			Likely benign (Jul 21, 2023)
6-104744142-C-T			Likely benign (Aug 01, 2022)
6-104744143-A-G			Likely benign (Feb 09, 2022)
6-104744155-C-T			Uncertain significance (Jul 09, 2022)
6-104744162-G-C			Likely benign (Aug 22, 2022)
6-104744165-C-T			Uncertain significance (Nov 30, 2021)
6-104744179-A-G			Likely benign (Aug 18, 2022)
6-104744180-GAGA-G		Spastic paraplegia-severe developmental delay-epilepsy syndrome	Uncertain significance (Mar 11, 2023)
6-104744206-T-C			Uncertain significance (May 27, 2022)
6-104744210-T-C			Likely benign (Apr 22, 2022)
6-104744232-TAAC-T		Spastic paraplegia-severe developmental delay-epilepsy syndrome	Benign (Jan 31, 2024)
6-104744238-C-G			Likely benign (Dec 30, 2023)
6-104744244-C-CA			Benign (Mar 24, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HACE1	protein_coding	protein_coding	ENST00000262903	24	131827

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000608	1.00	125701	0	47	125748	0.000187

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.59	259	481	0.539	0.0000240	6004
Missense in Polyphen		64	162.29	0.39435		2056
Synonymous	-0.475	175	167	1.05	0.00000835	1681
Loss of Function	4.35	19	53.2	0.357	0.00000268	631

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000297	0.000297
Ashkenazi Jewish	0.00	0.00
East Asian	0.000381	0.000381
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000158	0.000158
Middle Eastern	0.000381	0.000381
South Asian	0.000360	0.000359
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: E3 ubiquitin-protein ligase involved in Golgi membrane fusion and regulation of small GTPases. Acts as a regulator of Golgi membrane dynamics during the cell cycle: recruited to Golgi membrane by Rab proteins and regulates postmitotic Golgi membrane fusion. Acts by mediating ubiquitination during mitotic Golgi disassembly, ubiquitination serving as a signal for Golgi reassembly later, after cell division. Specifically interacts with GTP-bound RAC1, mediating ubiquitination and subsequent degradation of active RAC1, thereby playing a role in host defense against pathogens. May also act as a transcription regulator via its interaction with RARB. {ECO:0000269|PubMed:15254018, ECO:0000269|PubMed:21988917, ECO:0000269|PubMed:22036506}.
• Disease: DISEASE: Note=Defects in HACE1 are a cause of Wilms tumor (WT). WT is a pediatric malignancy of kidney and one of the most common solid cancers in childhood. HACE1 is epigenetically down-regulated in sporadic Wilms tumor. Moreover, a t(5;6)(q21;q21) translocation that truncates HACE1 has been found in a child with bilateral, young-onset Wilms tumor (PubMed:19948536). {ECO:0000269|PubMed:17694067, ECO:0000269|PubMed:19948536}.; DISEASE: Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS) [MIM:616756]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPPRS is an autosomal recessive neurodevelopmental disorder manifesting in infancy. Affected individuals show hypotonia and psychomotor retardation. Most develop seizures. {ECO:0000269|PubMed:26424145, ECO:0000269|PubMed:26437029}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation (Consensus)

Recessive Scores

• pRec: 0.103

Intolerance Scores

• loftool: 0.680
• rvis_EVS: -0.91
• rvis_percentile_EVS: 9.96

Haploinsufficiency Scores

• pHI: 0.206
• hipred: Y
• hipred_score: 0.706
• ghis: 0.624

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.267

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hace1
• Phenotype: skeleton phenotype; neoplasm; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: hace1
• Affected structure: atrioventricular canal
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: protein polyubiquitination;ubiquitin-dependent protein catabolic process;Golgi organization;cell cycle;protein ubiquitination;Rac protein signal transduction;regulation of cell migration;membrane fusion;protein K48-linked ubiquitination
• Cellular component: Golgi membrane;nucleus;cytoplasm;endoplasmic reticulum;nuclear body;Golgi cisterna membrane
• Molecular function: ubiquitin-protein transferase activity;protein binding;Rab GTPase binding;Rac GTPase binding;ubiquitin protein ligase activity