22-29273723-C-G

Variant names:

• chr22-29273723-C-G
• rs55801595
• NM_005243.4:c.103-18C>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.103-18C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.071 in 1,597,402 control chromosomes in the GnomAD database, including 4,622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (357 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4265 hom.)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.785
• Publications: 2 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 22-29273723-C-G is Benign according to our data. Variant chr22-29273723-C-G is described in ClinVar as [Benign]. Clinvar id is 1249698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EWSR1	NM_005243.4	c.103-18C>G		intron_variant	Intron 3 of 16	ENST00000397938.7	NP_005234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EWSR1	ENST00000397938.7	c.103-18C>G		intron_variant	Intron 3 of 16	1	NM_005243.4	ENSP00000381031.2

Frequencies

GnomAD3 genomes AF: 0.0570 AC: 8650 AN: 151696 Hom.: 357 Cov.: 32

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.0892

Gnomad AMR AF: 0.0503

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0125

Gnomad FIN AF: 0.0743

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0865

Gnomad OTH AF: 0.0518

GnomAD2 exomes AF: 0.0587 AC: 13946 AN: 237496 AF XY: 0.0584

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0326

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0000565

Gnomad FIN exome AF: 0.0684

Gnomad NFE exome AF: 0.0869

Gnomad OTH exome AF: 0.0715

GnomAD4 exome AF: 0.0725 AC: 104826 AN: 1445590 Hom.: 4265 Cov.: 33 AF XY: 0.0711 AC XY: 51086 AN XY: 718702

African (AFR) AF: 0.0119 AC: 389 AN: 32762

American (AMR) AF: 0.0338 AC: 1398 AN: 41362

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2699 AN: 25528

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39512

South Asian (SAS) AF: 0.0154 AC: 1268 AN: 82540

European-Finnish (FIN) AF: 0.0720 AC: 3822 AN: 53120

Middle Eastern (MID) AF: 0.0626 AC: 299 AN: 4780

European-Non Finnish (NFE) AF: 0.0824 AC: 91130 AN: 1106366

Other (OTH) AF: 0.0640 AC: 3817 AN: 59620

GnomAD4 genome AF: 0.0570 AC: 8652 AN: 151812 Hom.: 357 Cov.: 32 AF XY: 0.0548 AC XY: 4067 AN XY: 74164

African (AFR) AF: 0.0143 AC: 594 AN: 41484

American (AMR) AF: 0.0502 AC: 766 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 365 AN: 3466

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

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4800

European-Finnish (FIN) AF: 0.0743 AC: 775 AN: 10426

Middle Eastern (MID) AF: 0.0788 AC: 23 AN: 292

European-Non Finnish (NFE) AF: 0.0865 AC: 5876 AN: 67900

Other (OTH) AF: 0.0513 AC: 108 AN: 2106

Alfa AF: 0.0584 Hom.: 74

Bravo AF: 0.0542

Asia WGS AF: 0.0110 AC: 40 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.14
DANN	Benign	0.42
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55801595; hg19: chr22-29669712;