HERC1
protein-codingHECT 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
Gene summary
This gen encodes a member of the HERC protein family. This protein stimulates guanine nucleotide exchange on ARF1 and Rab proteins. This protein may be involved in membrane transport processes. [provided by RefSeq, Mar 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~225.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014863
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014863
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0018710
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014863
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014863
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HERC1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003922.4. 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 | 6 | 382 | 12 | 400 | ||
| missense | 2 | 2 | 849 | 39 | 4 | 896 |
| nonsense | 15 | 13 | 5 | 33 | ||
| start loss | 0 | |||||
| frameshift | 8 | 10 | 18 | |||
| splice donor/acceptor (+/-2bp) | 8 | 11 | 19 | |||
| Total | 25 | 33 | 871 | 421 | 16 | 1366 |
Highest pathogenic variant AF is 0.000014252818
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003913.3 | 77 | MANE Select | |
| Ensembl | ENSP00000390158.2 | 77 | MANE Select | |
| Ensembl | ENSP00000453196.1 | 4 | Standard | |
| Ensembl | ENSP00000453086.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Ubiquitin mediated proteolysis - Homo sapiens (human)
- Immune System
- Adaptive Immune System
- Antigen processing: Ubiquitination & Proteasome degradation
- Class I MHC mediated antigen processing & presentation
Biological Process
- negative regulation of autophagy
- protein ubiquitination
- cerebellar Purkinje cell differentiation
- neuron projection development
- neuromuscular process controlling balance
Molecular Function
- ubiquitin-protein transferase activity
- ARF guanyl-nucleotide exchange factor activity
Cellular Component
- cytoplasm
- Golgi apparatus
- cytosol
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000443617
- Coding exons
- 77
- Length
- 225325
- Individuals with no LoFs
- 124612
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 55
- Defined
- 124667
- p
- 0.000221
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.96 | 1838 | 2.54e+3 | 0.723 | 0.000137 | 31354 |
| Missense (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 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00039 | 0.00039 | rare |
| Latino/Admixed American | 0.00028 | 0.00023 | rare |
| Ashkenazi Jewish | 0.00050 | 0.00050 | rare |
| East Asian | 0.00017 | 0.00017 | rare |
| Finnish | 0.000093 | 0.000093 | rare |
| European (Non-Finnish) | 0.00020 | 0.00019 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0.00052 | 0.00050 | rare |
dbNSFP Gene Annotations
Source:
- 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}.;
Recessive Scores
- pRec
- 0.120
Intolerance Scores
- LoFtool
- 0.652
- RVIS EVS
- -3.88
- RVIS percentile EVS
- 0.21
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.981
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | High |