rs3788410

Variant names:

• chr22-29274950-T-C
• rs3788410
• NM_005243.4:c.226+1086T>C

Variant summary

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

The NM_005243.4(EWSR1):​c.226+1086T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 152,128 control chromosomes in the GnomAD database, including 9,834 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 0.34 (9834 hom., cov: 32)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04
• Publications: 4 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EWSR1	NM_005243.4	c.226+1086T>C		intron_variant	Intron 4 of 16	ENST00000397938.7	NP_005234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EWSR1	ENST00000397938.7	c.226+1086T>C		intron_variant	Intron 4 of 16	1	NM_005243.4	ENSP00000381031.2

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51758 AN: 152010 Hom.: 9837 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.478

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.379

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

GnomAD4 genome AF: 0.340 AC: 51751 AN: 152128 Hom.: 9834 Cov.: 32 AF XY: 0.345 AC XY: 25661 AN XY: 74356

African (AFR) AF: 0.160 AC: 6636 AN: 41532

American (AMR) AF: 0.478 AC: 7297 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1617 AN: 3470

East Asian (EAS) AF: 0.303 AC: 1568 AN: 5178

South Asian (SAS) AF: 0.431 AC: 2077 AN: 4824

European-Finnish (FIN) AF: 0.386 AC: 4080 AN: 10568

Middle Eastern (MID) AF: 0.435 AC: 127 AN: 292

European-Non Finnish (NFE) AF: 0.401 AC: 27244 AN: 67972

Other (OTH) AF: 0.375 AC: 792 AN: 2112

Alfa AF: 0.371 Hom.: 2005

Bravo AF: 0.338

Asia WGS AF: 0.327 AC: 1137 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.4
DANN	Benign	0.73
PhyloP100		-1.0
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: rs3788410; hg19: chr22-29670939; COSMIC: COSV58425103; COSMIC: COSV58425103;