rs16987365

Variant names:

• chr22-29288171-A-G
• rs16987365
• NM_005243.4:c.794-435A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000397938.7(EWSR1):​c.794-435A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 152,352 control chromosomes in the GnomAD database, including 43 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 0.010 (43 hom., cov: 32)
• Consequence: EWSR1 ENST00000397938.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.243
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1532/152352) while in subpopulation AFR AF = 0.0355 (1477/41590). AF 95% confidence interval is 0.034. There are 43 homozygotes in GnomAd4. There are 741 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1532 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397938.7. 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.794-435A>G		intron	N/A	NP_005234.1
	EWSR1	NM_001438500.1		c.797-435A>G		intron	N/A	NP_001425429.1
	EWSR1	NM_001438528.1		c.794-435A>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.794-435A>G		intron	N/A	ENSP00000381031.2
	EWSR1	ENST00000406548.5	TSL:1	c.794-435A>G		intron	N/A	ENSP00000385726.1
	EWSR1	ENST00000332050.10	TSL:1	c.794-816A>G		intron	N/A	ENSP00000330896.7

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1533 AN: 152234 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00764

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

GnomAD4 genome AF: 0.0101 AC: 1532 AN: 152352 Hom.: 43 Cov.: 32 AF XY: 0.00994 AC XY: 741 AN XY: 74516

African (AFR) AF: 0.0355 AC: 1477 AN: 41590

American (AMR) AF: 0.00229 AC: 35 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68030

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00868 Hom.: 4

Bravo AF: 0.0112

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.21
DANN	Benign	0.35
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism

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: rs16987365; hg19: chr22-29684160;