rs11703595

Variant names:

• chr22-29289174-A-G
• rs11703595
• NM_005243.4:c.974+388A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005243.4(EWSR1):​c.974+388A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 242,288 control chromosomes in the GnomAD database, including 30 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 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.014 (13 hom.)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.912
• 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=-0.64).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0136 (1226/89974) while in subpopulation NFE AF = 0.0171 (966/56430). AF 95% confidence interval is 0.0162. There are 13 homozygotes in GnomAdExome4. There are 565 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1626 Unknown,AD gene.

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.974+388A>G		intron	N/A	NP_005234.1	Q01844-1
	EWSR1	NM_001438500.1		c.977+388A>G		intron	N/A	NP_001425429.1
	EWSR1	NM_001438528.1		c.974+388A>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.974+388A>G		intron	N/A	ENSP00000381031.2	Q01844-1
	EWSR1	ENST00000406548.5	TSL:1	c.974+388A>G		intron	N/A	ENSP00000385726.1	Q01844-3
	EWSR1	ENST00000332050.10	TSL:1	c.869+112A>G		intron	N/A	ENSP00000330896.7	C9JGE3

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1626 AN: 152196 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00781

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.0136 AC: 1226 AN: 89974 Hom.: 13 Cov.: 0 AF XY: 0.0135 AC XY: 565 AN XY: 41824

African (AFR) AF: 0.00191 AC: 8 AN: 4178

American (AMR) AF: 0.0138 AC: 42 AN: 3038

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 86 AN: 5376

East Asian (EAS) AF: 0.0000865 AC: 1 AN: 11562

South Asian (SAS) AF: 0.00192 AC: 2 AN: 1042

European-Finnish (FIN) AF: 0.00794 AC: 4 AN: 504

Middle Eastern (MID) AF: 0.00763 AC: 4 AN: 524

European-Non Finnish (NFE) AF: 0.0171 AC: 966 AN: 56430

Other (OTH) AF: 0.0154 AC: 113 AN: 7320

GnomAD4 genome AF: 0.0107 AC: 1626 AN: 152314 Hom.: 17 Cov.: 32 AF XY: 0.0101 AC XY: 756 AN XY: 74486

African (AFR) AF: 0.00260 AC: 108 AN: 41562

American (AMR) AF: 0.0153 AC: 234 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00781 AC: 83 AN: 10624

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0156 AC: 1058 AN: 68020

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.0144 Hom.: 28

Bravo AF: 0.0110

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.82
PhyloP100		0.91
Mutation Taster		=100/0	polymorphism

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: rs11703595; hg19: chr22-29685163; COSMIC: COSV58424889;