chr22-29292643-T-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001438500.1(EWSR1):​c.1167+37T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,368,836 control chromosomes in the GnomAD database, including 21,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1665 hom., cov: 32)
  • Exomes 𝑓: 0.17 (19398 hom.)
• Consequence: EWSR1 NM_001438500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-29292643-T-G is Benign according to our data. Variant chr22-29292643-T-G is described in ClinVar as Benign. ClinVar VariationId is 1280213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

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>G		intron	N/A	NP_005234.1
	EWSR1	NM_001438500.1		c.1167+37T>G		intron	N/A	NP_001425429.1
	EWSR1	NM_001438528.1		c.1164+37T>G		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>G		intron	N/A	ENSP00000381031.2
	EWSR1	ENST00000406548.5	TSL:1	c.1161+37T>G		intron	N/A	ENSP00000385726.1
	EWSR1	ENST00000332050.10	TSL:1	c.1056+37T>G		intron	N/A	ENSP00000330896.7

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19710 AN: 152090 Hom.: 1668 Cov.: 32

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.140

GnomAD2 exomes AF: 0.185 AC: 45709 AN: 247646 AF XY: 0.191

Gnomad AFR exome AF: 0.0288

Gnomad AMR exome AF: 0.242

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.197

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.171 AC: 207886 AN: 1216628 Hom.: 19398 Cov.: 15 AF XY: 0.175 AC XY: 107043 AN XY: 613058

African (AFR) AF: 0.0270 AC: 778 AN: 28808

American (AMR) AF: 0.226 AC: 9839 AN: 43542

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3411 AN: 24252

East Asian (EAS) AF: 0.198 AC: 7593 AN: 38254

South Asian (SAS) AF: 0.291 AC: 23203 AN: 79644

European-Finnish (FIN) AF: 0.199 AC: 10454 AN: 52580

Middle Eastern (MID) AF: 0.154 AC: 815 AN: 5284

European-Non Finnish (NFE) AF: 0.161 AC: 143393 AN: 892350

Other (OTH) AF: 0.162 AC: 8400 AN: 51914

GnomAD4 genome AF: 0.129 AC: 19702 AN: 152208 Hom.: 1665 Cov.: 32 AF XY: 0.135 AC XY: 10020 AN XY: 74408

African (AFR) AF: 0.0325 AC: 1350 AN: 41550

American (AMR) AF: 0.150 AC: 2296 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 516 AN: 3470

East Asian (EAS) AF: 0.192 AC: 993 AN: 5184

South Asian (SAS) AF: 0.305 AC: 1469 AN: 4820

European-Finnish (FIN) AF: 0.197 AC: 2085 AN: 10574

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10599 AN: 68008

Other (OTH) AF: 0.137 AC: 289 AN: 2112

Alfa AF: 0.144 Hom.: 3293

Bravo AF: 0.121

Asia WGS AF: 0.257 AC: 897 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.80
CADD	Benign	10
DANN	Benign	0.63
PhyloP100		3.5
PromoterAI		0.026	Neutral
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: rs3761426; hg19: chr22-29688632; COSMIC: COSV58421629; COSMIC: COSV58421629;