22-29286712-A-T

Variant names:

• chr22-29286712-A-T
• rs5997462
• NM_005243.4:c.582-211A>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.582-211A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 121,204 control chromosomes in the GnomAD database, including 3,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.22 (3002 hom., cov: 26)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.72
• 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: 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=-0.93).
• BP6: Variant 22-29286712-A-T is Benign according to our data. Variant chr22-29286712-A-T is described in ClinVar as Benign. ClinVar VariationId is 1248405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 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.582-211A>T		intron	N/A	NP_005234.1	Q01844-1
	EWSR1	NM_001438500.1		c.585-211A>T		intron	N/A	NP_001425429.1
	EWSR1	NM_001438528.1		c.582-211A>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.582-211A>T		intron	N/A	ENSP00000381031.2	Q01844-1
	EWSR1	ENST00000406548.5	TSL:1	c.582-211A>T		intron	N/A	ENSP00000385726.1	Q01844-3
	EWSR1	ENST00000332050.10	TSL:1	c.582-211A>T		intron	N/A	ENSP00000330896.7	C9JGE3

Frequencies

GnomAD3 genomes AF: 0.223 AC: 27061 AN: 121114 Hom.: 3000 Cov.: 26

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.0376

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.219

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.217

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

GnomAD4 genome AF: 0.224 AC: 27091 AN: 121204 Hom.: 3002 Cov.: 26 AF XY: 0.228 AC XY: 13296 AN XY: 58194

African (AFR) AF: 0.270 AC: 8577 AN: 31728

American (AMR) AF: 0.215 AC: 2529 AN: 11754

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 543 AN: 2956

East Asian (EAS) AF: 0.400 AC: 1737 AN: 4342

South Asian (SAS) AF: 0.390 AC: 1569 AN: 4018

European-Finnish (FIN) AF: 0.198 AC: 1352 AN: 6816

Middle Eastern (MID) AF: 0.212 AC: 48 AN: 226

European-Non Finnish (NFE) AF: 0.182 AC: 10339 AN: 56916

Other (OTH) AF: 0.222 AC: 367 AN: 1650

Alfa AF: 0.0457 Hom.: 42

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	-0.93
CADD	Benign	0.14
DANN	Benign	0.13
PhyloP100		-2.7
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: rs5997462; hg19: chr22-29682701;