22-29291980-TAA-T

Variant names:

• chr22-29291980-TAA-T
• rs72547475
• NM_005243.4:c.1013-155_1013-154delAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005243.4(EWSR1):​c.1013-155_1013-154delAA variant causes a intron change. The variant allele was found at a frequency of 0.00000718 in 557,368 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.25
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EWSR1	NM_005243.4	MANE Select	c.1013-155_1013-154delAA		intron	N/A	NP_005234.1
	EWSR1	NM_001438500.1		c.1016-155_1016-154delAA		intron	N/A	NP_001425429.1
	EWSR1	NM_001438528.1		c.1013-155_1013-154delAA		intron	N/A	NP_001425457.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EWSR1	ENST00000397938.7	TSL:1 MANE Select	c.1013-155_1013-154delAA		intron	N/A	ENSP00000381031.2
	EWSR1	ENST00000406548.5	TSL:1	c.1010-155_1010-154delAA		intron	N/A	ENSP00000385726.1
	EWSR1	ENST00000332050.10	TSL:1	c.905-155_905-154delAA		intron	N/A	ENSP00000330896.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000718 AC: 4 AN: 557368 Hom.: 0 AF XY: 0.00000674 AC XY: 2 AN XY: 296612

African (AFR) AF: 0.00 AC: 0 AN: 14736

American (AMR) AF: 0.00 AC: 0 AN: 26492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16294

East Asian (EAS) AF: 0.0000296 AC: 1 AN: 33794

South Asian (SAS) AF: 0.00 AC: 0 AN: 52544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2650

European-Non Finnish (NFE) AF: 0.00000890 AC: 3 AN: 337114

Other (OTH) AF: 0.00 AC: 0 AN: 29620

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.3

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: rs72547475; hg19: chr22-29687969;