chr22-29282413-C-T

Variant names:

• chr22-29282413-C-T
• NM_005243.4:c.437C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005243.4(EWSR1):​c.437C>T​(p.Thr146Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EWSR1 NM_005243.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25102836).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005243.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EWSR1	NM_005243.4	MANE Select	c.437C>T	p.Thr146Ile	missense	Exon 6 of 17	NP_005234.1	Q01844-1
	EWSR1	NM_001438500.1		c.440C>T	p.Thr147Ile	missense	Exon 6 of 17	NP_001425429.1
	EWSR1	NM_001438528.1		c.437C>T	p.Thr146Ile	missense	Exon 6 of 17	NP_001425457.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EWSR1	ENST00000397938.7	TSL:1 MANE Select	c.437C>T	p.Thr146Ile	missense	Exon 6 of 17	ENSP00000381031.2	Q01844-1
	EWSR1	ENST00000406548.5	TSL:1	c.437C>T	p.Thr146Ile	missense	Exon 6 of 17	ENSP00000385726.1	Q01844-3
	EWSR1	ENST00000332050.10	TSL:1	c.437C>T	p.Thr146Ile	missense	Exon 6 of 17	ENSP00000330896.7	C9JGE3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1442422 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 717216

African (AFR) AF: 0.00 AC: 0 AN: 32222

American (AMR) AF: 0.00 AC: 0 AN: 39772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25708

East Asian (EAS) AF: 0.00 AC: 0 AN: 38840

South Asian (SAS) AF: 0.00 AC: 0 AN: 82060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105380

Other (OTH) AF: 0.00 AC: 0 AN: 59640

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.0	L
PhyloP100		1.7
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.20		Loss of glycosylation at T146 (P = 0.0084)
MVP		0.83
MPC		0.92
ClinPred		0.64	D
GERP RS		5.1
Varity_R		0.18
gMVP		0.26
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chr22-29678402;