rs140065

Positions:

• chr22-29296498-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005243.4(EWSR1):​c.1294+130G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 1,045,356 control chromosomes in the GnomAD database, including 340,432 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51835 hom., cov: 31)
  • Exomes 𝑓: 0.80 (288597 hom.)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.202

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 22-29296498-G-T is Benign according to our data. Variant chr22-29296498-G-T is described in ClinVar as [Benign]. Clinvar id is 1280487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EWSR1	NM_005243.4	c.1294+130G>T		intron_variant		ENST00000397938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EWSR1	ENST00000397938.7	c.1294+130G>T		intron_variant		1	NM_005243.4	P4

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125017 AN: 151672 Hom.: 51778 Cov.: 31

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.574

Gnomad AMR AF: 0.838

Gnomad ASJ AF: 0.835

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.898

Gnomad FIN AF: 0.805

Gnomad MID AF: 0.809

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.810

GnomAD4 exome AF: 0.801 AC: 715764 AN: 893564 Hom.: 288597 AF XY: 0.803 AC XY: 364947 AN XY: 454274

Gnomad4 AFR exome AF: 0.887

Gnomad4 AMR exome AF: 0.887

Gnomad4 ASJ exome AF: 0.848

Gnomad4 EAS exome AF: 0.961

Gnomad4 SAS exome AF: 0.896

Gnomad4 FIN exome AF: 0.812

Gnomad4 NFE exome AF: 0.775

Gnomad4 OTH exome AF: 0.807

GnomAD4 genome AF: 0.824 AC: 125134 AN: 151792 Hom.: 51835 Cov.: 31 AF XY: 0.828 AC XY: 61424 AN XY: 74210

Gnomad4 AFR AF: 0.883

Gnomad4 AMR AF: 0.838

Gnomad4 ASJ AF: 0.835

Gnomad4 EAS AF: 0.959

Gnomad4 SAS AF: 0.899

Gnomad4 FIN AF: 0.805

Gnomad4 NFE AF: 0.776

Gnomad4 OTH AF: 0.812

Alfa AF: 0.808 Hom.: 7250

Bravo AF: 0.828

Asia WGS AF: 0.936 AC: 3257 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.9
DANN	Benign	0.58

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: rs140065; hg19: chr22-29692488;