rs2857461

Variant names:

• chr22-29272015-C-T
• rs2857461
• NM_005243.4:c.14-201C>T

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.14-201C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.98 in 152,316 control chromosomes in the GnomAD database, including 73,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.98 (73213 hom., cov: 31)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.461
• Publications: 4 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=-0.88).
• BP6: Variant 22-29272015-C-T is Benign according to our data. Variant chr22-29272015-C-T is described in ClinVar as Benign. ClinVar VariationId is 1220856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.14-201C>T		intron	N/A	NP_005234.1	Q01844-1
	EWSR1	NM_001438500.1		c.14-201C>T		intron	N/A	NP_001425429.1
	EWSR1	NM_001438528.1		c.14-201C>T		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.14-201C>T		intron	N/A	ENSP00000381031.2	Q01844-1
	EWSR1	ENST00000406548.5	TSL:1	c.14-201C>T		intron	N/A	ENSP00000385726.1	Q01844-3
	EWSR1	ENST00000332050.10	TSL:1	c.14-201C>T		intron	N/A	ENSP00000330896.7	C9JGE3

Frequencies

GnomAD3 genomes AF: 0.980 AC: 149222 AN: 152198 Hom.: 73156 Cov.: 31

Gnomad AFR AF: 0.984

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.983

Gnomad ASJ AF: 0.991

Gnomad EAS AF: 0.988

Gnomad SAS AF: 0.960

Gnomad FIN AF: 0.980

Gnomad MID AF: 0.991

Gnomad NFE AF: 0.977

Gnomad OTH AF: 0.980

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.980 AC: 149338 AN: 152316 Hom.: 73213 Cov.: 31 AF XY: 0.980 AC XY: 72980 AN XY: 74482

African (AFR) AF: 0.984 AC: 40911 AN: 41558

American (AMR) AF: 0.983 AC: 15041 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.991 AC: 3442 AN: 3472

East Asian (EAS) AF: 0.988 AC: 5120 AN: 5182

South Asian (SAS) AF: 0.960 AC: 4633 AN: 4826

European-Finnish (FIN) AF: 0.980 AC: 10411 AN: 10620

Middle Eastern (MID) AF: 0.990 AC: 291 AN: 294

European-Non Finnish (NFE) AF: 0.977 AC: 66506 AN: 68040

Other (OTH) AF: 0.981 AC: 2071 AN: 2112

Alfa AF: 0.979 Hom.: 17792

Bravo AF: 0.981

Asia WGS AF: 0.971 AC: 3378 AN: 3478

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	-0.88
CADD	Benign	5.2
DANN	Benign	0.19
PhyloP100		0.46
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: rs2857461; hg19: chr22-29668004;