chr22-29273704-T-C

Variant names:

• chr22-29273704-T-C
• rs4820804
• NM_005243.4:c.103-37T>C

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.103-37T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 1,596,820 control chromosomes in the GnomAD database, including 125,698 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10382 hom., cov: 32)
  • Exomes 𝑓: 0.40 (115316 hom.)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0220
• Publications: 17 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=-0.85).
• BP6: Variant 22-29273704-T-C is Benign according to our data. Variant chr22-29273704-T-C is described in ClinVar as [Benign]. Clinvar id is 1276860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EWSR1	NM_005243.4	c.103-37T>C		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.103-37T>C		intron_variant	Intron 3 of 16	1	NM_005243.4	ENSP00000381031.2

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54164 AN: 151992 Hom.: 10383 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.392

GnomAD2 exomes AF: 0.403 AC: 96510 AN: 239494 AF XY: 0.407

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.500

Gnomad ASJ exome AF: 0.496

Gnomad EAS exome AF: 0.291

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.403

Gnomad OTH exome AF: 0.417

GnomAD4 exome AF: 0.396 AC: 571428 AN: 1444710 Hom.: 115316 Cov.: 31 AF XY: 0.399 AC XY: 286382 AN XY: 717818

African (AFR) AF: 0.197 AC: 6451 AN: 32682

American (AMR) AF: 0.504 AC: 20988 AN: 41662

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 12613 AN: 25622

East Asian (EAS) AF: 0.296 AC: 11694 AN: 39530

South Asian (SAS) AF: 0.455 AC: 37705 AN: 82796

European-Finnish (FIN) AF: 0.387 AC: 20570 AN: 53182

Middle Eastern (MID) AF: 0.465 AC: 2007 AN: 4314

European-Non Finnish (NFE) AF: 0.394 AC: 435501 AN: 1105368

Other (OTH) AF: 0.401 AC: 23899 AN: 59554

GnomAD4 genome AF: 0.356 AC: 54165 AN: 152110 Hom.: 10382 Cov.: 32 AF XY: 0.361 AC XY: 26849 AN XY: 74346

African (AFR) AF: 0.207 AC: 8592 AN: 41512

American (AMR) AF: 0.486 AC: 7430 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 1650 AN: 3466

East Asian (EAS) AF: 0.302 AC: 1564 AN: 5176

South Asian (SAS) AF: 0.446 AC: 2144 AN: 4812

European-Finnish (FIN) AF: 0.385 AC: 4069 AN: 10564

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27452 AN: 67980

Other (OTH) AF: 0.387 AC: 819 AN: 2114

Alfa AF: 0.401 Hom.: 21671

Bravo AF: 0.355

Asia WGS AF: 0.341 AC: 1185 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	-0.85
CADD	Benign	2.2
DANN	Benign	0.36
PhyloP100		-0.022
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: rs4820804; hg19: chr22-29669693; COSMIC: COSV58421406; COSMIC: COSV58421406;