22-29273723-C-G

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.103-18C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.071 in 1,597,402 control chromosomes in the GnomAD database, including 4,622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.057 (357 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4265 hom.)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.785

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=-0.8).
• BP6: Variant 22-29273723-C-G is Benign according to our data. Variant chr22-29273723-C-G is described in ClinVar as [Benign]. Clinvar id is 1249698.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-29273723-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EWSR1	NM_005243.4	c.103-18C>G		intron_variant		ENST00000397938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EWSR1	ENST00000397938.7	c.103-18C>G		intron_variant		1	NM_005243.4	P4

Frequencies

GnomAD3 genomes AF: 0.0570 AC: 8650 AN: 151696 Hom.: 357 Cov.: 32

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.0892

Gnomad AMR AF: 0.0503

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0125

Gnomad FIN AF: 0.0743

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0865

Gnomad OTH AF: 0.0518

GnomAD3 exomes AF: 0.0587 AC: 13946 AN: 237496 Hom.: 566 AF XY: 0.0584 AC XY: 7488 AN XY: 128192

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0326

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0000565

Gnomad SAS exome AF: 0.0132

Gnomad FIN exome AF: 0.0684

Gnomad NFE exome AF: 0.0869

Gnomad OTH exome AF: 0.0715

GnomAD4 exome AF: 0.0725 AC: 104826 AN: 1445590 Hom.: 4265 Cov.: 33 AF XY: 0.0711 AC XY: 51086 AN XY: 718702

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.0338

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0154

Gnomad4 FIN exome AF: 0.0720

Gnomad4 NFE exome AF: 0.0824

Gnomad4 OTH exome AF: 0.0640

GnomAD4 genome AF: 0.0570 AC: 8652 AN: 151812 Hom.: 357 Cov.: 32 AF XY: 0.0548 AC XY: 4067 AN XY: 74164

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.0502

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.0743

Gnomad4 NFE AF: 0.0865

Gnomad4 OTH AF: 0.0513

Alfa AF: 0.0584 Hom.: 74

Bravo AF: 0.0542

Asia WGS AF: 0.0110 AC: 40 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	-0.80
Cadd	Benign	0.14
Dann	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55801595; hg19: chr22-29669712;