22-29272015-C-T

Position:

• chr22-29272015-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005243.4(EWSR1):​c.14-201C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.98 in 152,316 control chromosomes in the GnomAD database, including 73,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.98 (73213 hom., cov: 31)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.461

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-29272015-C-T is Benign according to our data. Variant chr22-29272015-C-T is described in ClinVar as [Benign]. Clinvar id is 1220856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EWSR1	NM_005243.4	c.14-201C>T		intron_variant		ENST00000397938.7	NP_005234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EWSR1	ENST00000397938.7	c.14-201C>T		intron_variant		1	NM_005243.4	ENSP00000381031	P4

Frequencies

GnomAD3 genomes AF: 0.980 AC: 149222 AN: 152198 Hom.: 73156 Cov.: 31

Gnomad AFR AF: 0.984

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.983

Gnomad ASJ AF: 0.991

Gnomad EAS AF: 0.988

Gnomad SAS AF: 0.960

Gnomad FIN AF: 0.980

Gnomad MID AF: 0.991

Gnomad NFE AF: 0.977

Gnomad OTH AF: 0.980

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

GnomAD4 genome AF: 0.980 AC: 149338 AN: 152316 Hom.: 73213 Cov.: 31 AF XY: 0.980 AC XY: 72980 AN XY: 74482

Gnomad4 AFR AF: 0.984

Gnomad4 AMR AF: 0.983

Gnomad4 ASJ AF: 0.991

Gnomad4 EAS AF: 0.988

Gnomad4 SAS AF: 0.960

Gnomad4 FIN AF: 0.980

Gnomad4 NFE AF: 0.977

Gnomad4 OTH AF: 0.981

Alfa AF: 0.979 Hom.: 17792

Bravo AF: 0.981

Asia WGS AF: 0.971 AC: 3378 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.2
DANN	Benign	0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs2857461; hg19: chr22-29668004;