rs5763131

Positions:

• chr22-29289763-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005243.4(EWSR1):​c.974+977A>G variant causes a intron 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 NM_005243.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.156

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
EWSR1	NM_005243.4	c.974+977A>G		intron_variant		ENST00000397938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EWSR1	ENST00000397938.7	c.974+977A>G		intron_variant		1	NM_005243.4	P4

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

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.191

Gnomad4 EAS exome AF: 0.363

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.172

Gnomad4 NFE exome AF: 0.174

Gnomad4 OTH exome AF: 0.169

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

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.126

Gnomad4 ASJ AF: 0.192

Gnomad4 EAS AF: 0.296

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.184

Gnomad4 OTH AF: 0.169

Alfa AF: 0.179 Hom.: 1441

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

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

Publications

LitVar

Other links and lift over

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