22-29299939-T-G

Position:

• chr22-29299939-T-G

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.1931+88T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,534,244 control chromosomes in the GnomAD database, including 17,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1449 hom., cov: 28)
  • Exomes 𝑓: 0.15 (15628 hom.)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.266

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=-0.94).
• BP6: Variant 22-29299939-T-G is Benign according to our data. Variant chr22-29299939-T-G is described in ClinVar as [Benign]. Clinvar id is 1268712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EWSR1	NM_005243.4	c.1931+88T>G		intron_variant		ENST00000397938.7	NP_005234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EWSR1	ENST00000397938.7	c.1931+88T>G		intron_variant		1	NM_005243.4	ENSP00000381031	P4

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20071 AN: 149006 Hom.: 1449 Cov.: 28

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0353

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.145 AC: 200919 AN: 1385116 Hom.: 15628 Cov.: 29 AF XY: 0.146 AC XY: 99725 AN XY: 683544

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.0987

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.0329

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.145

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.135 AC: 20078 AN: 149128 Hom.: 1449 Cov.: 28 AF XY: 0.134 AC XY: 9743 AN XY: 72694

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.0352

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.158

Alfa AF: 0.113 Hom.: 397

Bravo AF: 0.135

Asia WGS AF: 0.0650 AC: 227 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 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.46
DANN	Benign	0.31

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: rs2518683; hg19: chr22-29695929;