22-29273840-ACT-GCG

Variant names:

• chr22-29273840-ACT-GCG
• NM_005243.4:c.202_204delACTinsGCG
• EWSR1 p.Thr68Ala

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005243.4(EWSR1):​c.202_204delACTinsGCG​(p.Thr68Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EWSR1 NM_005243.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.42
• Publications: 0 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: AD, Unknown Classification: MODERATE, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.202_204delACTinsGCG	p.Thr68Ala	missense	N/A	NP_005234.1	Q01844-1
	EWSR1	NM_001438500.1		c.205_207delACTinsGCG	p.Thr69Ala	missense	N/A	NP_001425429.1
	EWSR1	NM_001438528.1		c.202_204delACTinsGCG	p.Thr68Ala	missense	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.202_204delACTinsGCG	p.Thr68Ala	missense	N/A	ENSP00000381031.2	Q01844-1
	EWSR1	ENST00000406548.5	TSL:1	c.202_204delACTinsGCG	p.Thr68Ala	missense	N/A	ENSP00000385726.1	Q01844-3
	EWSR1	ENST00000332050.10	TSL:1	c.202_204delACTinsGCG	p.Thr68Ala	missense	N/A	ENSP00000330896.7	C9JGE3

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr22-29669829;