HERC1

HECT and RLD domain containing E3 ubiquitin protein ligase family member 1, the group of WD repeat domain containing|HECT and RLD domain containing E3 ubiquitin protein ligases

Basic information

Region (hg38): 15:63608618-63833948

Links

ENSG00000103657 ∙ NCBI:8925 ∙ OMIM:605109 ∙ HGNC:4867 ∙ Uniprot:Q15751 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• macrocephaly, dysmorphic facies, and psychomotor retardation (Moderate), mode of inheritance: AR
• macrocephaly, dysmorphic facies, and psychomotor retardation (Strong), mode of inheritance: AR
• megalencephaly-severe kyphoscoliosis-overgrowth syndrome (Supportive), mode of inheritance: AR
• macrocephaly, dysmorphic facies, and psychomotor retardation (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Macrocephaly, dysmorphic facies, and psychomotor retardation	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	26138117; 26153217; 27108999

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HERC1 gene.

• not_provided (1166 variants)
• Inborn_genetic_diseases (522 variants)
• Macrocephaly,_dysmorphic_facies,_and_psychomotor_retardation (70 variants)
• HERC1-related_disorder (55 variants)
• not_specified (31 variants)
• See_cases (3 variants)
• Neurodevelopmental_disorder (2 variants)
• Megalencephaly_with_thick_corpus_callosum,_cerebellar_atrophy,_and_intellectual_disability (2 variants)
• Premature_ovarian_insufficiency (2 variants)
• Intellectual_disability (2 variants)
• Multiple_congenital_anomalies/dysmorphic_syndrome (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HERC1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000003922.4. 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			6	358	15	379
missense	2	2	815	37	4	860
nonsense	15	10	5			30
start loss						0
frameshift	8	7	1			16
splice donor/acceptor (+/-2bp)		8	11			19
Total	25	27	838	395	19

Highest pathogenic variant AF is 0.000014252818

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HERC1	protein_coding	protein_coding	ENST00000443617	77	225325

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		124612	0	55	124667	0.000221

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.96	1838	2.54e+3	0.723	0.000137	31354
Missense in Polyphen		646	1154.3	0.55967		14099
Synonymous	-0.588	958	935	1.02	0.0000502	9763
Loss of Function	11.8	46	245	0.187	0.0000142	2903

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000668	0.000667
Ashkenazi Jewish	0.000499	0.000497
East Asian	0.000167	0.000167
Finnish	0.0000928	0.0000928
European (Non-Finnish)	0.000197	0.000195
Middle Eastern	0.000167	0.000167
South Asian	0.000203	0.000196
Other	0.000517	0.000495

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in membrane trafficking via some guanine nucleotide exchange factor (GEF) activity and its ability to bind clathrin. Acts as a GEF for Arf and Rab, by exchanging bound GDP for free GTP. Binds phosphatidylinositol 4,5-bisphosphate, which is required for GEF activity. May also act as a E3 ubiquitin- protein ligase which accepts ubiquitin from an E2 ubiquitin- conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. {ECO:0000269|PubMed:15642342, ECO:0000269|PubMed:8861955, ECO:0000269|PubMed:9233772}.
• Pathway: Ubiquitin mediated proteolysis - Homo sapiens (human);Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation (Consensus)

Recessive Scores

• pRec: 0.120

Intolerance Scores

• loftool: 0.652
• rvis_EVS: -3.88
• rvis_percentile_EVS: 0.21

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.981

Gene Damage Prediction

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

Gene ontology

• Biological process: negative regulation of autophagy;protein ubiquitination;cerebellar Purkinje cell differentiation;neuron projection development;neuromuscular process controlling balance
• Cellular component: cytoplasm;Golgi apparatus;cytosol;membrane
• Molecular function: ubiquitin-protein transferase activity;ARF guanyl-nucleotide exchange factor activity