rs131184

Variant names:

• chr22-29285227-A-G
• rs131184
• NM_005243.4:c.582-1696A>G

Variant summary

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

The NM_005243.4(EWSR1):​c.582-1696A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 148,352 control chromosomes in the GnomAD database, including 1,265 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 0.12 (1265 hom., cov: 29)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.14
• Publications: 5 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005243.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EWSR1	NM_005243.4	MANE Select	c.582-1696A>G		intron	N/A	NP_005234.1
	EWSR1	NM_001438500.1		c.585-1696A>G		intron	N/A	NP_001425429.1
	EWSR1	NM_001438528.1		c.582-1696A>G		intron	N/A	NP_001425457.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EWSR1	ENST00000397938.7	TSL:1 MANE Select	c.582-1696A>G		intron	N/A	ENSP00000381031.2
	EWSR1	ENST00000406548.5	TSL:1	c.582-1696A>G		intron	N/A	ENSP00000385726.1
	EWSR1	ENST00000332050.10	TSL:1	c.582-1696A>G		intron	N/A	ENSP00000330896.7

Frequencies

GnomAD3 genomes AF: 0.119 AC: 17580 AN: 148234 Hom.: 1265 Cov.: 29

Gnomad AFR AF: 0.0971

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.0406

Gnomad SAS AF: 0.0945

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.132

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.119 AC: 17584 AN: 148352 Hom.: 1265 Cov.: 29 AF XY: 0.118 AC XY: 8500 AN XY: 72314

African (AFR) AF: 0.0969 AC: 3775 AN: 38938

American (AMR) AF: 0.125 AC: 1865 AN: 14912

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 404 AN: 3464

East Asian (EAS) AF: 0.0405 AC: 206 AN: 5086

South Asian (SAS) AF: 0.0943 AC: 450 AN: 4770

European-Finnish (FIN) AF: 0.111 AC: 1131 AN: 10166

Middle Eastern (MID) AF: 0.193 AC: 56 AN: 290

European-Non Finnish (NFE) AF: 0.135 AC: 9173 AN: 67748

Other (OTH) AF: 0.130 AC: 270 AN: 2070

Alfa AF: 0.118 Hom.: 219

Bravo AF: 0.120

Asia WGS AF: 0.0590 AC: 204 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.31
DANN	Benign	0.33
PhyloP100		-2.1
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: rs131184; hg19: chr22-29681216;