rs17194186

Variant names:

• chr21-38595152-C-T
• rs17194186
• ENST00000398919.6:c.-149-10207G>A

Variant summary

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

The ENST00000398919.6(ERG):​c.-149-10207G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 151,914 control chromosomes in the GnomAD database, including 2,117 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 0.16 (2117 hom., cov: 32)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• Publications: 4 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_001136154.1	c.-149-10207G>A		intron_variant	Intron 1 of 11		NP_001129626.1
ERG	NM_001243428.1	c.-149-10207G>A		intron_variant	Intron 1 of 11		NP_001230357.1
ERG	NM_004449.4	c.-149-10207G>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.-149-10207G>A		intron_variant	Intron 1 of 11	1		ENSP00000381891.2
ERG	ENST00000468474.5	n.38-10207G>A		intron_variant	Intron 1 of 7	1
ERG	ENST00000485493.1	n.38-10207G>A		intron_variant	Intron 1 of 4	1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24534 AN: 151796 Hom.: 2112 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.146

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

GnomAD4 genome AF: 0.162 AC: 24559 AN: 151914 Hom.: 2117 Cov.: 32 AF XY: 0.164 AC XY: 12137 AN XY: 74232

African (AFR) AF: 0.114 AC: 4709 AN: 41418

American (AMR) AF: 0.146 AC: 2235 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 520 AN: 3472

East Asian (EAS) AF: 0.290 AC: 1486 AN: 5128

South Asian (SAS) AF: 0.253 AC: 1212 AN: 4798

European-Finnish (FIN) AF: 0.189 AC: 1993 AN: 10546

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11990 AN: 67944

Other (OTH) AF: 0.145 AC: 307 AN: 2114

Alfa AF: 0.172 Hom.: 8923

Bravo AF: 0.155

Asia WGS AF: 0.241 AC: 842 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.031
DANN	Benign	0.63
PhyloP100		-2.0
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: rs17194186; hg19: chr21-39967076;