22-29273659-G-C

Position:

• chr22-29273659-G-C

Variant summary

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

The ENST00000397938.7(EWSR1):​c.103-82G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,459,576 control chromosomes in the GnomAD database, including 28,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3155 hom., cov: 33)
  • Exomes 𝑓: 0.19 (25357 hom.)
• Consequence: EWSR1 ENST00000397938.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.639

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=-0.8).
• BP6: Variant 22-29273659-G-C is Benign according to our data. Variant chr22-29273659-G-C is described in ClinVar as [Benign]. Clinvar id is 1270867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EWSR1	NM_005243.4	c.103-82G>C		intron_variant		ENST00000397938.7	NP_005234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EWSR1	ENST00000397938.7	c.103-82G>C		intron_variant		1	NM_005243.4	ENSP00000381031	P4

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29360 AN: 151616 Hom.: 3148 Cov.: 33

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.192

GnomAD4 exome AF: 0.186 AC: 243074 AN: 1307846 Hom.: 25357 AF XY: 0.191 AC XY: 124074 AN XY: 650394

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.363

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.294

Gnomad4 SAS exome AF: 0.366

Gnomad4 FIN exome AF: 0.196

Gnomad4 NFE exome AF: 0.165

Gnomad4 OTH exome AF: 0.192

GnomAD4 genome AF: 0.194 AC: 29376 AN: 151730 Hom.: 3155 Cov.: 33 AF XY: 0.202 AC XY: 14980 AN XY: 74120

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.307

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.301

Gnomad4 SAS AF: 0.363

Gnomad4 FIN AF: 0.194

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.190

Alfa AF: 0.0880 Hom.: 125

Bravo AF: 0.198

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	-0.80
CADD	Benign	7.0
DANN	Benign	0.71

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: rs4820803; hg19: chr22-29669648;