Genetic Variant EWSR1:c.226+406G>A (chr22-29274270-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013986.4(EWSR1):c.232G>A(p.Gly78Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

EWSR1
NM_013986.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.18

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25839317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EWSR1	NM_005243.4 link	c.226+406G>A		intron_variant	Intron 4 of 16	ENST00000397938.7	NP_005234.1	Q01844-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EWSR1	ENST00000397938.7 link	c.226+406G>A		intron_variant	Intron 4 of 16	1	NM_005243.4	ENSP00000381031.2		Q01844-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000201

AC:

AN:

248800

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000278

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33476

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44722

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26132

Gnomad4 EAS exome

AF:

0.000101

AC:

AN:

39680

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86256

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53396

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1111812

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60368

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.232G>A (p.G78R) alteration is located in exon 5 (coding exon 5) of the EWSR1 gene. This alteration results from a G to A substitution at nucleotide position 232, causing the glycine (G) at amino acid position 78 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

.;T;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.69

T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.25

Sift

Uncertain

0.015

D;D;D

Sift4G

Benign

0.22

T;D;D

Vest4

0.48

MutPred

0.22

.;Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);

MVP

0.55

MPC

1.6

ClinPred

0.56

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

gMVP

0.37

Mutation Taster

=77/23

polymorphism

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over