chr22-29279412-A-G

Variant names:

• chr22-29279412-A-G
• rs140062
• NM_005243.4:c.413+1196A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005243.4(EWSR1):​c.413+1196A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 152,126 control chromosomes in the GnomAD database, including 9,695 homozygotes. 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: 𝑓 0.33 (9695 hom., cov: 32)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.328
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.463 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EWSR1	NM_005243.4	MANE Select	c.413+1196A>G		intron	N/A	NP_005234.1
	EWSR1	NM_001438500.1		c.416+1196A>G		intron	N/A	NP_001425429.1
	EWSR1	NM_001438528.1		c.413+1196A>G		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.413+1196A>G		intron	N/A	ENSP00000381031.2
	EWSR1	ENST00000406548.5	TSL:1	c.413+1196A>G		intron	N/A	ENSP00000385726.1
	EWSR1	ENST00000332050.10	TSL:1	c.413+1196A>G		intron	N/A	ENSP00000330896.7

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49819 AN: 152008 Hom.: 9699 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.364

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

GnomAD4 genome AF: 0.327 AC: 49804 AN: 152126 Hom.: 9695 Cov.: 32 AF XY: 0.333 AC XY: 24733 AN XY: 74382

African (AFR) AF: 0.103 AC: 4258 AN: 41536

American (AMR) AF: 0.472 AC: 7208 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1616 AN: 3470

East Asian (EAS) AF: 0.299 AC: 1551 AN: 5180

South Asian (SAS) AF: 0.421 AC: 2030 AN: 4818

European-Finnish (FIN) AF: 0.392 AC: 4144 AN: 10570

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27810 AN: 67956

Other (OTH) AF: 0.360 AC: 760 AN: 2112

Alfa AF: 0.327 Hom.: 1812

Bravo AF: 0.322

Asia WGS AF: 0.318 AC: 1106 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.74
DANN	Benign	0.43
PhyloP100		0.33
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: rs140062; hg19: chr22-29675401;