NM_005243.4:c.400A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005243.4(EWSR1):c.400A>G(p.Thr134Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

EWSR1
NM_005243.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.535

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis
Inheritance: Unknown, AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

EWSR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05991143).

BS2

High AC in GnomAdExome4 at 24 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EWSR1	NM_005243.4 link	c.400A>G	p.Thr134Ala	missense_variant	Exon 5 of 17	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.400A>G	p.Thr134Ala	missense_variant	Exon 5 of 17	1	NM_005243.4	ENSP00000381031.2		Q01844-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

250540

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461690

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.000112

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1111918

Other (OTH)

AF:

0.0000662

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.000196

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.418A>G (p.T140A) alteration is located in exon 6 (coding exon 6) of the EWSR1 gene. This alteration results from a A to G substitution at nucleotide position 418, causing the threonine (T) at amino acid position 140 to be replaced by an alanine (A). 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

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.024

T;T;T;.;T;.;T;T;T;.;.;T;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.76

T;T;T;T;T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.060

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.46

.;.;N;.;.;N;.;.;.;.;N;.;N

PhyloP100

0.54

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.9

N;.;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.074

Sift

Benign

0.18

T;.;T;T;T;T;T;T;T;T;T;T;D

Sift4G

Benign

0.22

T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0

.;.;B;.;.;.;.;.;.;.;.;.;.

Vest4

0.29

MutPred

0.23

Loss of glycosylation at T134 (P = 0.0067);.;Loss of glycosylation at T134 (P = 0.0067);.;.;Loss of glycosylation at T134 (P = 0.0067);.;.;Loss of glycosylation at T134 (P = 0.0067);.;Loss of glycosylation at T134 (P = 0.0067);Loss of glycosylation at T134 (P = 0.0067);Loss of glycosylation at T134 (P = 0.0067);

MVP

0.86

MPC

0.63

ClinPred

0.039

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.068

gMVP

0.13

Mutation Taster

=86/14

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_005243.4:c.400A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over