rs9613855

Variant names:

• chr22-29276304-A-G
• rs9613855
• NM_005243.4:c.227-1726A>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.227-1726A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0668 in 229,682 control chromosomes in the GnomAD database, including 755 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 0.067 (498 hom., cov: 32)
  • Exomes 𝑓: 0.067 (257 hom.)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 4 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0955 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EWSR1	NM_005243.4	MANE Select	c.227-1726A>G		intron	N/A	NP_005234.1	Q01844-1
	EWSR1	NM_001438500.1		c.230-1726A>G		intron	N/A	NP_001425429.1
	EWSR1	NM_001438528.1		c.227-1726A>G		intron	N/A	NP_001425457.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EWSR1	ENST00000397938.7	TSL:1 MANE Select	c.227-1726A>G		intron	N/A	ENSP00000381031.2	Q01844-1
	EWSR1	ENST00000406548.5	TSL:1	c.227-1726A>G		intron	N/A	ENSP00000385726.1	Q01844-3
	EWSR1	ENST00000332050.10	TSL:1	c.227-1726A>G		intron	N/A	ENSP00000330896.7	C9JGE3

Frequencies

GnomAD3 genomes AF: 0.0668 AC: 10168 AN: 152156 Hom.: 498 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.0601

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0898

Gnomad OTH AF: 0.0598

GnomAD4 exome AF: 0.0668 AC: 5172 AN: 77408 Hom.: 257 Cov.: 0 AF XY: 0.0664 AC XY: 2367 AN XY: 35624

African (AFR) AF: 0.0147 AC: 55 AN: 3730

American (AMR) AF: 0.0672 AC: 160 AN: 2382

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 228 AN: 4918

East Asian (EAS) AF: 0.0000924 AC: 1 AN: 10826

South Asian (SAS) AF: 0.0968 AC: 66 AN: 682

European-Finnish (FIN) AF: 0.161 AC: 9 AN: 56

Middle Eastern (MID) AF: 0.0745 AC: 35 AN: 470

European-Non Finnish (NFE) AF: 0.0874 AC: 4181 AN: 47852

Other (OTH) AF: 0.0673 AC: 437 AN: 6492

GnomAD4 genome AF: 0.0668 AC: 10166 AN: 152274 Hom.: 498 Cov.: 32 AF XY: 0.0704 AC XY: 5243 AN XY: 74446

African (AFR) AF: 0.0159 AC: 660 AN: 41580

American (AMR) AF: 0.0600 AC: 918 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 169 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5186

South Asian (SAS) AF: 0.103 AC: 497 AN: 4824

European-Finnish (FIN) AF: 0.152 AC: 1614 AN: 10588

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0898 AC: 6105 AN: 68008

Other (OTH) AF: 0.0587 AC: 124 AN: 2114

Alfa AF: 0.0817 Hom.: 1127

Bravo AF: 0.0582

Asia WGS AF: 0.0440 AC: 156 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.36
DANN	Benign	0.81
PhyloP100		-1.1
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: rs9613855; hg19: chr22-29672293;