rs9613855

Variant names:

• chr22-29276304-A-G
• rs9613855
• NM_005243.4:c.227-1726A>G

Variant summary

Our verdict is Benign. Variant got -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

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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EWSR1	NM_005243.4	c.227-1726A>G		intron_variant	Intron 4 of 16	ENST00000397938.7	NP_005234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EWSR1	ENST00000397938.7	c.227-1726A>G		intron_variant	Intron 4 of 16	1	NM_005243.4	ENSP00000381031.2

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

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.0672

Gnomad4 ASJ exome AF: 0.0464

Gnomad4 EAS exome AF: 0.0000924

Gnomad4 SAS exome AF: 0.0968

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.0874

Gnomad4 OTH exome AF: 0.0673

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

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.0600

Gnomad4 ASJ AF: 0.0487

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.0898

Gnomad4 OTH AF: 0.0587

Alfa AF: 0.0828 Hom.: 835

Bravo AF: 0.0582

Asia WGS AF: 0.0440 AC: 156 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.36
DANN	Benign	0.81

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: rs9613855; hg19: chr22-29672293;