22-29286914-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005243.4(EWSR1):c.582-9C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 1,589,418 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (18 hom.)
• Consequence: EWSR1 NM_005243.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008784
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0550

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 22-29286914-C-G is Benign according to our data. Variant chr22-29286914-C-G is described in ClinVar as [Benign]. Clinvar id is 773619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 457 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EWSR1	NM_005243.4	c.582-9C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000397938.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EWSR1	ENST00000397938.7	c.582-9C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005243.4	P4

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 457 AN: 150542 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000953

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00398

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00199

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00386

GnomAD3 exomes AF: 0.00283 AC: 684 AN: 241320 Hom.: 6 AF XY: 0.00285 AC XY: 372 AN XY: 130514

Gnomad AFR exome AF: 0.000565

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00187

Gnomad NFE exome AF: 0.00440

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00388 AC: 5589 AN: 1438764 Hom.: 18 Cov.: 32 AF XY: 0.00386 AC XY: 2761 AN XY: 715956

Gnomad4 AFR exome AF: 0.000555

Gnomad4 AMR exome AF: 0.00355

Gnomad4 ASJ exome AF: 0.00102

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000335

Gnomad4 FIN exome AF: 0.00158

Gnomad4 NFE exome AF: 0.00455

Gnomad4 OTH exome AF: 0.00448

GnomAD4 genome AF: 0.00303 AC: 457 AN: 150654 Hom.: 1 Cov.: 32 AF XY: 0.00282 AC XY: 207 AN XY: 73492

Gnomad4 AFR AF: 0.000950

Gnomad4 AMR AF: 0.00397

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00199

Gnomad4 NFE AF: 0.00475

Gnomad4 OTH AF: 0.00382

Alfa AF: 0.00296 Hom.: 0

Bravo AF: 0.00315

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ewing sarcoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 08, 2019

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	6.6
Dann	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000088
dbscSNV1_RF	Benign	0.0080
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: rs189387468; hg19: chr22-29682903; COSMIC: COSV105202265; COSMIC: COSV105202265;