22-29292643-T-C

Variant names:

• chr22-29292643-T-C
• rs3761426
• NM_005243.4:c.1164+37T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001438500.1(EWSR1):​c.1167+37T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EWSR1 NM_001438500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.51
• Publications: 18 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438500.1. 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.1164+37T>C		intron	N/A	NP_005234.1
	EWSR1	NM_001438500.1		c.1167+37T>C		intron	N/A	NP_001425429.1
	EWSR1	NM_001438528.1		c.1164+37T>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.1164+37T>C		intron	N/A	ENSP00000381031.2
	EWSR1	ENST00000406548.5	TSL:1	c.1161+37T>C		intron	N/A	ENSP00000385726.1
	EWSR1	ENST00000332050.10	TSL:1	c.1056+37T>C		intron	N/A	ENSP00000330896.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 15

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 3293

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	10
DANN	Benign	0.68
PhyloP100		3.5
PromoterAI		0.016	Neutral

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: rs3761426; hg19: chr22-29688632;