22-29299939-T-G

Variant names:

• chr22-29299939-T-G
• rs2518683
• NM_005243.4:c.1931+88T>G

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.1931+88T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,534,244 control chromosomes in the GnomAD database, including 17,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1449 hom., cov: 28)
  • Exomes 𝑓: 0.15 (15628 hom.)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.266
• Publications: 11 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

ENSG00000301612 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 22-29299939-T-G is Benign according to our data. Variant chr22-29299939-T-G is described in ClinVar as Benign. ClinVar VariationId is 1268712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 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.1931+88T>G		intron	N/A	NP_005234.1
	EWSR1	NM_001438500.1		c.1973+88T>G		intron	N/A	NP_001425429.1
	EWSR1	NM_001438528.1		c.1970+88T>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.1931+88T>G		intron	N/A	ENSP00000381031.2
	EWSR1	ENST00000406548.5	TSL:1	c.1928+88T>G		intron	N/A	ENSP00000385726.1
	EWSR1	ENST00000332050.10	TSL:1	c.1823+88T>G		intron	N/A	ENSP00000330896.7

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20071 AN: 149006 Hom.: 1449 Cov.: 28

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0353

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.145 AC: 200919 AN: 1385116 Hom.: 15628 Cov.: 29 AF XY: 0.146 AC XY: 99725 AN XY: 683544

African (AFR) AF: 0.109 AC: 3386 AN: 31126

American (AMR) AF: 0.0987 AC: 3240 AN: 32826

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3058 AN: 22094

East Asian (EAS) AF: 0.0329 AC: 1282 AN: 38924

South Asian (SAS) AF: 0.121 AC: 9224 AN: 76544

European-Finnish (FIN) AF: 0.145 AC: 7398 AN: 51066

Middle Eastern (MID) AF: 0.204 AC: 953 AN: 4672

European-Non Finnish (NFE) AF: 0.153 AC: 164249 AN: 1070980

Other (OTH) AF: 0.143 AC: 8129 AN: 56884

GnomAD4 genome AF: 0.135 AC: 20078 AN: 149128 Hom.: 1449 Cov.: 28 AF XY: 0.134 AC XY: 9743 AN XY: 72694

African (AFR) AF: 0.107 AC: 4289 AN: 40120

American (AMR) AF: 0.137 AC: 2054 AN: 14948

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 522 AN: 3458

East Asian (EAS) AF: 0.0352 AC: 177 AN: 5028

South Asian (SAS) AF: 0.109 AC: 505 AN: 4612

European-Finnish (FIN) AF: 0.148 AC: 1524 AN: 10310

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.155 AC: 10419 AN: 67394

Other (OTH) AF: 0.158 AC: 326 AN: 2066

Alfa AF: 0.141 Hom.: 2768

Bravo AF: 0.135

Asia WGS AF: 0.0650 AC: 227 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	-0.94
CADD	Benign	0.46
DANN	Benign	0.31
PhyloP100		-0.27
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: rs2518683; hg19: chr22-29695929;