chr22-29273778-C-T

Variant names:

• chr22-29273778-C-T
• rs959758730
• NM_005243.4:c.140C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005243.4(EWSR1):​c.140C>T​(p.Pro47Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,696 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P47H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EWSR1 NM_005243.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.97
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EWSR1	NM_005243.4	c.140C>T	p.Pro47Leu	missense_variant	Exon 4 of 17	ENST00000397938.7	NP_005234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EWSR1	ENST00000397938.7	c.140C>T	p.Pro47Leu	missense_variant	Exon 4 of 17	1	NM_005243.4	ENSP00000381031.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461696 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111936

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T;T;D;.;T;.;T;T;.;.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.9	.;.;.;M;.;.;M;.;.;M;M;.;M
PhyloP100		6.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.5	D;D;.;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D;D;.;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.79, 0.84, 0.59, 0.70, 0.63, 0.73, 0.92, 0.81
MutPred		0.44		.;Gain of catalytic residue at P47 (P = 0.0028);.;Gain of catalytic residue at P47 (P = 0.0028);.;.;Gain of catalytic residue at P47 (P = 0.0028);.;Gain of catalytic residue at P47 (P = 0.0028);Gain of catalytic residue at P47 (P = 0.0028);Gain of catalytic residue at P47 (P = 0.0028);Gain of catalytic residue at P47 (P = 0.0028);Gain of catalytic residue at P47 (P = 0.0028);
MVP		0.60
MPC		1.4
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.55
gMVP		0.50
Mutation Taster		=37/63	disease causing

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: rs959758730; hg19: chr22-29669767;