EWSR1
protein-codingEWS RNA binding protein 1, the group of RNA binding motif containing|Zinc fingers RANBP2-type
Gene summary
This gene encodes a multifunctional protein that is involved in various cellular processes, including gene expression, cell signaling, and RNA processing and transport. The protein includes an N-terminal transcriptional activation domain and a C-terminal RNA-binding domain. Chromosomal translocations between this gene and various genes encoding transcription factors result in the production of chimeric proteins that are involved in tumorigenesis. These chimeric proteins usually consist of the N-terminal transcriptional activation domain of this protein fused to the C-terminal DNA-binding domain of the transcription factor protein. Mutations in this gene, specifically a t(11;22)(q24;q12) translocation, are known to cause Ewing sarcoma as well as neuroectodermal and various other tumors. Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 1 and 14. [provided by RefSeq, Jul 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~32.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0004976
Submitter: ClinGen
EWSR1 was first reported in relation to amyotrophic lateral sclerosis (ALS) of undetermined inheritance in 2012 (Couthouis et al., PMID: 22454397). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities; amyotrophic lateral sclerosis and Ewing sarcoma/neuroepithlioma (OMIM: 612219). The split curation for ALS of undetermined inheritance has been curated separately. Four missense variants that have been reported in four probands in two publications (PMIDs: 22454397, 25299611) are included in this curation. We classified EWSR1 as of undetermined inheritance as we couldn't identify if any variants segregated with disease as parental information was unavailable. We determined that the mechanism of pathogenicity appears to be loss of function (heterozygous). There were four variants which were evaluated but not scored (G512A, P533L, G585S, Y190F) as their population specific allele frequencies were above the ALS GCEP threshold. One of these variants (G585S) was also present in an individual that was harboring a C9orf72 gene expansion, therefore it is unclear whether this variant contributed to the ALS phenotype. This gene-disease association is refuted by several lines of experimental data. Evidence supporting EWSR1 as being a binding partner of FUS and TAF15 was not scored as technical elements of the experiment were questionable (PMID:23975937). Experiments showing the functional impact of the P553L variant on cytoplasmic localisation in rat and mouse primary neurons was not scored as we determined that this variant was not causal for ALS based on genetic evidence (PMID: 22454397). Furthermore, the levels of retinal degeneration and expression of EWSR1 observed in a Drosophila model system were similar between wild type and mutants (PMID: 22454397). Also, neurodegenerative/ALS-like phenotypes observed in homozygous knockout mouse models (PMID: 29731676) and mouse embryonic fibroblasts (PMID: 25946189) do not adequately reflect the human ALS phenotype as heterozygous missense EWSR1 variants are thought to be responsible. The gene-disease association is supported by in vitro functional assays which implicate soluble wild-type EWSR1 as participating in key ALS associated processes such as aggregation and cytoplasmic localisation (PMID: 22454397). In summary, the evidence supporting the relationship between EWSR1 and ALS has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role EWSR1 plays in this disease. This classification was approved by the ClinGen ALS GCEP on the meeting date October 11, 2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0004976
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0004976
Submitter: Genomics England PanelApp
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to EWSR1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005243.4. 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 | 2 | 5 | 3 | 10 | ||
| missense | 61 | 3 | 64 | |||
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 8 | 8 | ||||
| Total | 0 | 0 | 73 | 8 | 3 | 84 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005234.1 | 17 | MANE Select | |
| Ensembl | ENSP00000381031.2 | 17 | MANE Select | |
| RefSeq | NP_001156757.1 | 17 | Standard | |
| RefSeq | NP_001156758.1 | 16 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ewsr1a | Danio rerio | Structure: cell Quality: structure abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Transcriptional misregulation in cancer - Homo sapiens (human)
- TGF_beta_Receptor
- BARD1 signaling events
Biological Process
- regulation of transcription, DNA-templated
Molecular Function
- RNA binding
- protein binding
- calmodulin binding
- identical protein binding
- metal ion binding
Cellular Component
- nucleus
- nucleolus
- cytoplasm
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000414183
- Coding exons
- 18
- Length
- 32518
- Individuals with no LoFs
- 125718
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 30
- Defined
- 125748
- p
- 0.000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.52 | 256 | 398 | 0.644 | 0.0000227 | 4236 |
| Missense (PolyPhen) | 32 | 56.778 | 0.5636 | 722 | ||
| Synonymous | -1.49 | 156 | 134 | 1.16 | 0.00000713 | 1334 |
| Loss of Function | 5.44 | 4 | 42.0 | 0.0952 | 0.00000229 | 456 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00020 | 0.00018 | rare |
| Latino/Admixed American | 0.00017 | 0.00014 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000058 | 0.000054 | rare |
| Finnish | 0.00010 | 0.000092 | rare |
| European (Non-Finnish) | 0.00015 | 0.00015 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Might normally function as a transcriptional repressor. EWS-fusion-proteins (EFPS) may play a role in the tumorigenic process. They may disturb gene expression by mimicking, or interfering with the normal function of CTD-POLII within the transcription initiation complex. They may also contribute to an aberrant activation of the fusion protein target genes.;
- Disease
- DISEASE: Ewing sarcoma (ES) [MIM:612219]: A highly malignant, metastatic, primitive small round cell tumor of bone and soft tissue that affects children and adolescents. It belongs to the Ewing sarcoma family of tumors, a group of morphologically heterogeneous neoplasms that share the same cytogenetic features. They are considered neural tumors derived from cells of the neural crest. Ewing sarcoma represents the less differentiated form of the tumors. {ECO:0000269|PubMed:15044653, ECO:0000269|PubMed:1522903, ECO:0000269|PubMed:7700648, ECO:0000269|PubMed:9121764}. Note=The protein represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving EWSR1 are found in patients with Ewing sarcoma. Translocation t(11;22)(q24;q12) with FLI1 (PubMed:1522903, PubMed:15044653). Translocation t(7;22)(p22;q12) with ETV1 (PubMed:7700648). Translocation t(21;22)(q22;q21) with ERG (PubMed:15044653). Translocation t(2;21;22)(q23;q22;q12) that forms a EWSR1-FEV fusion protein with potential oncogenic activity (PubMed:9121764). {ECO:0000269|PubMed:15044653, ECO:0000269|PubMed:1522903, ECO:0000269|PubMed:7700648, ECO:0000269|PubMed:9121764}.; DISEASE: Note=A chromosomal aberration involving EWSR1 has been found in extraskeletal myxoid chondrosarcoma. Translocation t(9;22)(q22-31;q11-12) with NR4A3. {ECO:0000269|PubMed:7539287}.; DISEASE: Note=A chromosomal aberration involving EWSR1 is associated with desmoplastic small round cell tumor (DSRCT). Translocation t(11;22)(p13;q12) with WT1. {ECO:0000269|PubMed:7862627}.; DISEASE: Note=A chromosomal aberration involving EWSR1 is associated with malignant melanoma of soft parts (MMSP). Translocation t(12;22)(q13;q12) with ATF1. Malignant melanoma of soft parts, also known as soft tissue clear cell sarcoma, is a rare tumor developing in tendons and aponeuroses. {ECO:0000269|PubMed:8401579}.; DISEASE: Note=A chromosomal aberration involving EWSR1 is associated with small round cell sarcoma. Translocation t(11;22)(p36.1;q12) with PATZ1. {ECO:0000269|PubMed:10949935}.; DISEASE: Angiomatoid fibrous histiocytoma (AFH) [MIM:612160]: A distinct variant of malignant fibrous histiocytoma that typically occurs in children and adolescents and is manifest by nodular subcutaneous growth. Characteristic microscopic features include lobulated sheets of histiocyte-like cells intimately associated with areas of hemorrhage and cystic pseudovascular spaces, as well as a striking cuffing of inflammatory cells, mimicking a lymph node metastasis. {ECO:0000269|PubMed:15884099, ECO:0000269|PubMed:17724745}. Note=The gene represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving EWSR1 are found in patients with angiomatoid fibrous histiocytoma. Translocation t(12;22)(q13;q12) with ATF1 generates a chimeric EWSR1/ATF1 protein (PubMed:15884099). Translocation t(2;22)(q33;q12) with CREB1 generates a EWSR1/CREB1 fusion gene that is most common genetic abnormality in this tumor type (PubMed:17724745). {ECO:0000269|PubMed:15884099, ECO:0000269|PubMed:17724745}.; DISEASE: Note=EFPS arise due to chromosomal translocations in which EWSR1 is fused to a variety of cellular transcription factors. EFPS are very potent transcriptional activators dependent on the EAD and a C-terminal DNA-binding domain contributed by the fusion partner. The spectrum of malignancies associated with EFPS are thought to arise via EFP-induced transcriptional deregulation, with the tumor phenotype specified by the EWSR1 fusion partner and cell type. Transcriptional repression of the transforming growth factor beta type II receptor (TGF beta RII) is an important target of the EWS-FLI1, EWS-ERG, or EWS-ETV1 oncogene. {ECO:0000305}.;
Recessive Scores
- pRec
- 0.431
Intolerance Scores
- LoFtool
- 0.0688
- RVIS EVS
- -0.78
- RVIS percentile EVS
- 12.88
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.884
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |