22-29273704-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005243.4(EWSR1):c.103-37T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 1,596,820 control chromosomes in the GnomAD database, including 125,698 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (10382 hom., cov: 32)
  • Exomes 𝑓: 0.40 (115316 hom.)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0220

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 22-29273704-T-C is Benign according to our data. Variant chr22-29273704-T-C is described in ClinVar as [Benign]. Clinvar id is 1276860.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EWSR1	NM_005243.4	c.103-37T>C		intron_variant		ENST00000397938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EWSR1	ENST00000397938.7	c.103-37T>C		intron_variant		1	NM_005243.4	P4

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54164 AN: 151992 Hom.: 10383 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.392

GnomAD3 exomes AF: 0.403 AC: 96510 AN: 239494 Hom.: 20302 AF XY: 0.407 AC XY: 52666 AN XY: 129258

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.500

Gnomad ASJ exome AF: 0.496

Gnomad EAS exome AF: 0.291

Gnomad SAS exome AF: 0.457

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.403

Gnomad OTH exome AF: 0.417

GnomAD4 exome AF: 0.396 AC: 571428 AN: 1444710 Hom.: 115316 Cov.: 31 AF XY: 0.399 AC XY: 286382 AN XY: 717818

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.504

Gnomad4 ASJ exome AF: 0.492

Gnomad4 EAS exome AF: 0.296

Gnomad4 SAS exome AF: 0.455

Gnomad4 FIN exome AF: 0.387

Gnomad4 NFE exome AF: 0.394

Gnomad4 OTH exome AF: 0.401

GnomAD4 genome AF: 0.356 AC: 54165 AN: 152110 Hom.: 10382 Cov.: 32 AF XY: 0.361 AC XY: 26849 AN XY: 74346

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.486

Gnomad4 ASJ AF: 0.476

Gnomad4 EAS AF: 0.302

Gnomad4 SAS AF: 0.446

Gnomad4 FIN AF: 0.385

Gnomad4 NFE AF: 0.404

Gnomad4 OTH AF: 0.387

Alfa AF: 0.407 Hom.: 17620

Bravo AF: 0.355

Asia WGS AF: 0.341 AC: 1185 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	2.2
Dann	Benign	0.36

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: rs4820804; hg19: chr22-29669693; COSMIC: COSV58421406; COSMIC: COSV58421406;