NM_005243.4:c.13+85G>A

Variant names:

• chr22-29268434-G-A
• rs2301291
• NM_005243.4:c.13+85G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005243.4(EWSR1):​c.13+85G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,611,450 control chromosomes in the GnomAD database, including 103,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9457 hom., cov: 33)
  • Exomes 𝑓: 0.35 (93837 hom.)
• Consequence: EWSR1 NM_005243.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.205
• Publications: 10 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]

RHBDD3 (HGNC:1308): (rhomboid domain containing 3) Predicted to enable serine-type endopeptidase activity. Predicted to be involved in proteolysis. Predicted to act upstream of or within several processes, including liver development; negative regulation of natural killer cell activation; and positive regulation of protein catabolic process. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 22-29268434-G-A is Benign according to our data. Variant chr22-29268434-G-A is described in ClinVar as [Benign]. Clinvar id is 1246240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EWSR1	NM_005243.4	c.13+85G>A		intron_variant	Intron 1 of 16	ENST00000397938.7	NP_005234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EWSR1	ENST00000397938.7	c.13+85G>A		intron_variant	Intron 1 of 16	1	NM_005243.4	ENSP00000381031.2

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52378 AN: 152018 Hom.: 9428 Cov.: 33

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.329

GnomAD4 exome AF: 0.352 AC: 513354 AN: 1459316 Hom.: 93837 AF XY: 0.353 AC XY: 256028 AN XY: 726008

African (AFR) AF: 0.324 AC: 10833 AN: 33454

American (AMR) AF: 0.358 AC: 15979 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 8675 AN: 26118

East Asian (EAS) AF: 0.657 AC: 26087 AN: 39690

South Asian (SAS) AF: 0.429 AC: 37019 AN: 86234

European-Finnish (FIN) AF: 0.395 AC: 20462 AN: 51856

Middle Eastern (MID) AF: 0.322 AC: 1845 AN: 5736

European-Non Finnish (NFE) AF: 0.334 AC: 371397 AN: 1111218

Other (OTH) AF: 0.349 AC: 21057 AN: 60316

GnomAD4 genome AF: 0.345 AC: 52454 AN: 152134 Hom.: 9457 Cov.: 33 AF XY: 0.349 AC XY: 25931 AN XY: 74392

African (AFR) AF: 0.326 AC: 13516 AN: 41510

American (AMR) AF: 0.303 AC: 4637 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1164 AN: 3470

East Asian (EAS) AF: 0.652 AC: 3364 AN: 5160

South Asian (SAS) AF: 0.448 AC: 2160 AN: 4822

European-Finnish (FIN) AF: 0.389 AC: 4116 AN: 10584

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.331 AC: 22505 AN: 67966

Other (OTH) AF: 0.337 AC: 711 AN: 2112

Alfa AF: 0.340 Hom.: 5834

Bravo AF: 0.337

Asia WGS AF: 0.567 AC: 1973 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.9
DANN	Benign	0.87
PhyloP100		0.20
PromoterAI		-0.044	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2301291; hg19: chr22-29664423; COSMIC: COSV53322570; COSMIC: COSV53322570;