EWSR1

EWS RNA binding protein 1, the group of RNA binding motif containing|Zinc fingers RANBP2-type

Basic information

Region (hg38): 22:29268008-29300525

Links

ENSG00000182944 ∙ NCBI:2130 ∙ OMIM:133450 ∙ HGNC:3508 ∙ Uniprot:Q01844 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• amyotrophic lateral sclerosis (Moderate), mode of inheritance: AD
• amyotrophic lateral sclerosis (Disputed Evidence), mode of inheritance: Unknown

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EWSR1 gene.

• not provided (27 variants)
• Inborn genetic diseases (12 variants)
• Amyotrophic lateral sclerosis (2 variants)
• Ewing sarcoma (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EWSR1 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				3	2	5
missense			13			13
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region				4		4
non coding					17	17
Total	0	0	13	3	19

Variants in EWSR1

This is a list of pathogenic ClinVar variants found in the EWSR1 region.

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

Position	Type	Phenotype	Significance	ClinVar
22-29268334-A-G		EWSR1-related disorder	Likely benign (May 02, 2019)
22-29268348-G-A		EWSR1-related disorder	Likely benign (Sep 09, 2019)
22-29268434-G-A			Benign (Jun 18, 2021)
22-29272015-C-T			Benign (Jun 18, 2021)
22-29272209-C-G			Likely benign (Dec 14, 2018)
22-29272384-A-G		not specified	Uncertain significance (Dec 13, 2022)
22-29273659-G-C			Benign (Jun 18, 2021)
22-29273704-T-C			Benign (Jun 18, 2021)
22-29273723-C-G			Benign (Jun 18, 2021)
22-29273778-C-A		not specified	Uncertain significance (Sep 22, 2023)
22-29273840-A-G		not specified	Uncertain significance (May 11, 2022)
22-29273848-T-C			Likely benign (Mar 01, 2023)
22-29274270-G-A		not specified	Uncertain significance (Oct 05, 2023)
22-29278031-T-A			Likely benign (May 29, 2018)
22-29278041-C-A			Uncertain significance (Feb 01, 2024)
22-29278047-G-A		not specified	Uncertain significance (Dec 20, 2022)
22-29278203-A-G		not specified	Uncertain significance (Oct 03, 2022)
22-29282488-G-C		not specified	Uncertain significance (Oct 13, 2023)
22-29286712-A-T			Benign (Jun 18, 2021)
22-29286914-C-G		Ewing sarcoma	Benign (Dec 31, 2019)
22-29286941-G-A			Benign (Dec 31, 2019)
22-29287056-A-G		not specified	Uncertain significance (Jun 16, 2023)
22-29287109-A-G		EWSR1-related disorder	Benign (Mar 28, 2019)
22-29291570-G-C		not specified	Uncertain significance (Oct 06, 2022)
22-29292142-A-G		not specified	Uncertain significance (Apr 25, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EWSR1	protein_coding	protein_coding	ENST00000414183	18	32518

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000195	125718	0	30	125748	0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.52	256	398	0.644	0.0000227	4236
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000373	0.000357
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000581	0.0000544
Finnish	0.000102	0.0000924
European (Non-Finnish)	0.000153	0.000149
Middle Eastern	0.0000581	0.0000544
South Asian	0.0000327	0.0000327
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• 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}.
• Pathway: Transcriptional misregulation in cancer - Homo sapiens (human);TGF_beta_Receptor;BARD1 signaling events (Consensus)

Recessive Scores

• pRec: 0.431

Intolerance Scores

• loftool: 0.0688
• rvis_EVS: -0.78
• rvis_percentile_EVS: 12.88

Haploinsufficiency Scores

• pHI: 0.956
• hipred: Y
• hipred_score: 0.783
• ghis: 0.658

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.884

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ewsr1
• Phenotype: adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); muscle phenotype; immune system phenotype; homeostasis/metabolism phenotype; cellular phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); neoplasm; hematopoietic system phenotype; normal phenotype; 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); reproductive system phenotype; limbs/digits/tail phenotype; hearing/vestibular/ear phenotype; renal/urinary system phenotype; skeleton phenotype

Zebrafish Information Network

• Gene name: ewsr1a
• Affected structure: cell
• Phenotype tag: abnormal
• Phenotype quality: structure

Gene ontology

• Biological process: regulation of transcription, DNA-templated
• Cellular component: nucleus;nucleolus;cytoplasm;plasma membrane
• Molecular function: RNA binding;protein binding;calmodulin binding;identical protein binding;metal ion binding