rs11703595

Positions:

• chr22-29289174-A-G

Variant summary

Our verdict is Benign. Variant got -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

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=-0.64).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 565 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1626 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EWSR1	NM_005243.4	c.974+388A>G		intron_variant		ENST00000397938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EWSR1	ENST00000397938.7	c.974+388A>G		intron_variant		1	NM_005243.4	P4

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

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.0138

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.0000865

Gnomad4 SAS exome AF: 0.00192

Gnomad4 FIN exome AF: 0.00794

Gnomad4 NFE exome AF: 0.0171

Gnomad4 OTH exome AF: 0.0154

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

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.0153

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00781

Gnomad4 NFE AF: 0.0156

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0145 Hom.: 3

Bravo AF: 0.0110

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.82

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