rs2836582

Variant names:

• chr21-38643384-C-T
• rs2836582
• ENST00000398919.6:c.-150+17138G>A

Variant summary

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

The ENST00000398919.6(ERG):​c.-150+17138G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 152,160 control chromosomes in the GnomAD database, including 3,135 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 0.19 (3135 hom., cov: 32)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.557
• Publications: 3 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_001136154.1	c.-150+18274G>A		intron_variant	Intron 1 of 11		NP_001129626.1
ERG	NM_001243428.1	c.-150+17138G>A		intron_variant	Intron 1 of 11		NP_001230357.1
ERG	NM_004449.4	c.-150+18274G>A		intron_variant	Intron 1 of 10		NP_004440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000398919.6	c.-150+17138G>A		intron_variant	Intron 1 of 11	1		ENSP00000381891.2
ERG	ENST00000468474.5	n.37+18274G>A		intron_variant	Intron 1 of 7	1
ERG	ENST00000485493.1	n.37+18274G>A		intron_variant	Intron 1 of 4	1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29423 AN: 152042 Hom.: 3135 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.215

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

GnomAD4 genome AF: 0.193 AC: 29424 AN: 152160 Hom.: 3135 Cov.: 32 AF XY: 0.187 AC XY: 13922 AN XY: 74412

African (AFR) AF: 0.133 AC: 5526 AN: 41514

American (AMR) AF: 0.157 AC: 2405 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 921 AN: 3468

East Asian (EAS) AF: 0.120 AC: 619 AN: 5174

South Asian (SAS) AF: 0.127 AC: 610 AN: 4818

European-Finnish (FIN) AF: 0.178 AC: 1892 AN: 10602

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.243 AC: 16506 AN: 67980

Other (OTH) AF: 0.214 AC: 453 AN: 2112

Alfa AF: 0.198 Hom.: 442

Bravo AF: 0.192

Asia WGS AF: 0.117 AC: 407 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.9
DANN	Benign	0.56
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2836582; hg19: chr21-40015308;