21-38431740-T-C

Variant names:

• chr21-38431740-T-C
• rs2836389
• NM_182918.4:c.237-8179A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182918.4(ERG):​c.237-8179A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 152,110 control chromosomes in the GnomAD database, including 5,769 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (5769 hom., cov: 32)
• Consequence: ERG NM_182918.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.719
• Publications: 1 publications found

Genes affected

ERG (HGNC:3446): (ETS transcription factor ERG) This gene encodes a member of the erythroblast transformation-specific (ETS) family of transcriptions factors. All members of this family are key regulators of embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis. The protein encoded by this gene is mainly expressed in the nucleus. It contains an ETS DNA-binding domain and a PNT (pointed) domain which is implicated in the self-association of chimeric oncoproteins. This protein is required for platelet adhesion to the subendothelium, inducing vascular cell remodeling. It also regulates hematopoesis, and the differentiation and maturation of megakaryocytic cells. This gene is involved in chromosomal translocations, resulting in different fusion gene products, such as TMPSSR2-ERG and NDRG1-ERG in prostate cancer, EWS-ERG in Ewing's sarcoma and FUS-ERG in acute myeloid leukemia. More than two dozens of transcript variants generated from combinatorial usage of three alternative promoters and multiple alternative splicing events have been reported, but the full-length nature of many of these variants has not been determined. [provided by RefSeq, Apr 2014]

ERG Gene-Disease associations (from GenCC):

• lymphatic malformation 14

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_182918.4	c.237-8179A>G		intron_variant	Intron 2 of 9	ENST00000288319.12	NP_891548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000288319.12	c.237-8179A>G		intron_variant	Intron 2 of 9	1	NM_182918.4	ENSP00000288319.7

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41435 AN: 151992 Hom.: 5754 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.283

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.273 AC: 41496 AN: 152110 Hom.: 5769 Cov.: 32 AF XY: 0.272 AC XY: 20229 AN XY: 74378

African (AFR) AF: 0.288 AC: 11940 AN: 41520

American (AMR) AF: 0.283 AC: 4319 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1086 AN: 3464

East Asian (EAS) AF: 0.307 AC: 1586 AN: 5164

South Asian (SAS) AF: 0.321 AC: 1545 AN: 4814

European-Finnish (FIN) AF: 0.216 AC: 2282 AN: 10580

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17675 AN: 67978

Other (OTH) AF: 0.291 AC: 612 AN: 2104

Alfa AF: 0.264 Hom.: 2836

Bravo AF: 0.279

Asia WGS AF: 0.345 AC: 1201 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.52
DANN	Benign	0.38
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

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: rs2836389; hg19: chr21-39803662;