rs2301291

Positions:

• chr22-29268434-G-A
• chr22-29268434-G-C

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.13+85G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,611,450 control chromosomes in the GnomAD database, including 103,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9457 hom., cov: 33)
  • Exomes 𝑓: 0.35 (93837 hom.)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.205

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=-0.84).
• BP6: Variant 22-29268434-G-A is Benign according to our data. Variant chr22-29268434-G-A is described in ClinVar as [Benign]. Clinvar id is 1246240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EWSR1	NM_005243.4	c.13+85G>A		intron_variant		ENST00000397938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EWSR1	ENST00000397938.7	c.13+85G>A		intron_variant		1	NM_005243.4	P4

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52378 AN: 152018 Hom.: 9428 Cov.: 33

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.329

GnomAD4 exome AF: 0.352 AC: 513354 AN: 1459316 Hom.: 93837 AF XY: 0.353 AC XY: 256028 AN XY: 726008

Gnomad4 AFR exome AF: 0.324

Gnomad4 AMR exome AF: 0.358

Gnomad4 ASJ exome AF: 0.332

Gnomad4 EAS exome AF: 0.657

Gnomad4 SAS exome AF: 0.429

Gnomad4 FIN exome AF: 0.395

Gnomad4 NFE exome AF: 0.334

Gnomad4 OTH exome AF: 0.349

GnomAD4 genome AF: 0.345 AC: 52454 AN: 152134 Hom.: 9457 Cov.: 33 AF XY: 0.349 AC XY: 25931 AN XY: 74392

Gnomad4 AFR AF: 0.326

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.335

Gnomad4 EAS AF: 0.652

Gnomad4 SAS AF: 0.448

Gnomad4 FIN AF: 0.389

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.337

Alfa AF: 0.332 Hom.: 2805

Bravo AF: 0.337

Asia WGS AF: 0.567 AC: 1973 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	-0.84
CADD	Benign	5.9
DANN	Benign	0.87

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: rs2301291; hg19: chr22-29664423; COSMIC: COSV53322570; COSMIC: COSV53322570;