22-29273659-G-C

Variant names:

• chr22-29273659-G-C
• rs4820803
• NM_005243.4:c.103-82G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005243.4(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 NM_005243.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.639
• Publications: 12 publications found

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]

EWSR1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: Unknown, AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005243.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EWSR1	NM_005243.4	MANE Select	c.103-82G>C		intron	N/A	NP_005234.1	Q01844-1
	EWSR1	NM_001438500.1		c.103-79G>C		intron	N/A	NP_001425429.1
	EWSR1	NM_001438528.1		c.103-82G>C		intron	N/A	NP_001425457.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EWSR1	ENST00000397938.7	TSL:1 MANE Select	c.103-82G>C		intron	N/A	ENSP00000381031.2	Q01844-1
	EWSR1	ENST00000406548.5	TSL:1	c.103-82G>C		intron	N/A	ENSP00000385726.1	Q01844-3
	EWSR1	ENST00000332050.10	TSL:1	c.103-82G>C		intron	N/A	ENSP00000330896.7	C9JGE3

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

African (AFR) AF: 0.161 AC: 4639 AN: 28858

American (AMR) AF: 0.363 AC: 10783 AN: 29698

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 2662 AN: 22132

East Asian (EAS) AF: 0.294 AC: 11162 AN: 37960

South Asian (SAS) AF: 0.366 AC: 27078 AN: 74036

European-Finnish (FIN) AF: 0.196 AC: 9919 AN: 50586

Middle Eastern (MID) AF: 0.199 AC: 722 AN: 3634

European-Non Finnish (NFE) AF: 0.165 AC: 165734 AN: 1006996

Other (OTH) AF: 0.192 AC: 10375 AN: 53946

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

African (AFR) AF: 0.166 AC: 6869 AN: 41374

American (AMR) AF: 0.307 AC: 4696 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 434 AN: 3462

East Asian (EAS) AF: 0.301 AC: 1554 AN: 5166

South Asian (SAS) AF: 0.363 AC: 1745 AN: 4804

European-Finnish (FIN) AF: 0.194 AC: 2025 AN: 10448

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11510 AN: 67892

Other (OTH) AF: 0.190 AC: 400 AN: 2106

Alfa AF: 0.0880 Hom.: 125

Bravo AF: 0.198

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.0
DANN	Benign	0.71
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4820803; hg19: chr22-29669648;