chr22-29281978-C-A

Variant names:

• chr22-29281978-C-A
• rs5752899
• NM_005243.4:c.414-412C>A

Variant summary

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

The NM_005243.4(EWSR1):​c.414-412C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 152,186 control chromosomes in the GnomAD database, including 1,888 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 0.15 (1888 hom., cov: 32)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0470
• Publications: 5 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EWSR1	NM_005243.4	c.414-412C>A		intron_variant	Intron 5 of 16	ENST00000397938.7	NP_005234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EWSR1	ENST00000397938.7	c.414-412C>A		intron_variant	Intron 5 of 16	1	NM_005243.4	ENSP00000381031.2

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22914 AN: 152068 Hom.: 1886 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.0765

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.142

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

GnomAD4 genome AF: 0.151 AC: 22942 AN: 152186 Hom.: 1888 Cov.: 32 AF XY: 0.148 AC XY: 11030 AN XY: 74398

African (AFR) AF: 0.108 AC: 4478 AN: 41524

American (AMR) AF: 0.107 AC: 1637 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 624 AN: 3472

East Asian (EAS) AF: 0.281 AC: 1453 AN: 5180

South Asian (SAS) AF: 0.0781 AC: 377 AN: 4830

European-Finnish (FIN) AF: 0.214 AC: 2266 AN: 10572

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11628 AN: 68000

Other (OTH) AF: 0.145 AC: 306 AN: 2114

Alfa AF: 0.153 Hom.: 950

Bravo AF: 0.143

Asia WGS AF: 0.166 AC: 577 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.0
DANN	Benign	0.72
PhyloP100		-0.047
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: rs5752899; hg19: chr22-29677967;