rs5763131

Variant names:

• chr22-29289763-A-G
• rs5763131
• ENST00000479135.5:n.4126A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000479135.5(EWSR1):​n.4126A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 232,014 control chromosomes in the GnomAD database, including 4,129 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.17 (2395 hom., cov: 33)
  • Exomes 𝑓: 0.20 (1734 hom.)
• Consequence: EWSR1 ENST00000479135.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.156
• Publications: 8 publications found

Genes affected

EWSR1 (HGNC:3508): (EWS RNA binding protein 1) 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]

EWSR1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: Unknown, AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EWSR1	NM_005243.4	c.974+977A>G		intron_variant	Intron 8 of 16	ENST00000397938.7	NP_005234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EWSR1	ENST00000397938.7	c.974+977A>G		intron_variant	Intron 8 of 16	1	NM_005243.4	ENSP00000381031.2

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26371 AN: 152106 Hom.: 2386 Cov.: 33

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.167

GnomAD4 exome AF: 0.198 AC: 15806 AN: 79790 Hom.: 1734 Cov.: 0 AF XY: 0.197 AC XY: 7220 AN XY: 36660

African (AFR) AF: 0.151 AC: 579 AN: 3840

American (AMR) AF: 0.133 AC: 328 AN: 2470

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 969 AN: 5070

East Asian (EAS) AF: 0.363 AC: 4029 AN: 11096

South Asian (SAS) AF: 0.108 AC: 75 AN: 696

European-Finnish (FIN) AF: 0.172 AC: 10 AN: 58

Middle Eastern (MID) AF: 0.167 AC: 81 AN: 484

European-Non Finnish (NFE) AF: 0.174 AC: 8607 AN: 49386

Other (OTH) AF: 0.169 AC: 1128 AN: 6690

GnomAD4 genome AF: 0.174 AC: 26411 AN: 152224 Hom.: 2395 Cov.: 33 AF XY: 0.172 AC XY: 12788 AN XY: 74428

African (AFR) AF: 0.151 AC: 6270 AN: 41530

American (AMR) AF: 0.126 AC: 1930 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 667 AN: 3468

East Asian (EAS) AF: 0.296 AC: 1536 AN: 5184

South Asian (SAS) AF: 0.117 AC: 564 AN: 4828

European-Finnish (FIN) AF: 0.227 AC: 2398 AN: 10586

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12509 AN: 68018

Other (OTH) AF: 0.169 AC: 358 AN: 2114

Alfa AF: 0.181 Hom.: 2152

Bravo AF: 0.167

Asia WGS AF: 0.201 AC: 696 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.92
DANN	Benign	0.69
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5763131; hg19: chr22-29685752; COSMIC: COSV58421252;