rs17194186

Positions:

• chr21-38595152-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ERG	NM_001136154.1	c.-149-10207G>A		intron_variant			NP_001129626.1
ERG	NM_001243428.1	c.-149-10207G>A		intron_variant			NP_001230357.1
ERG	NM_001243432.2	c.-149-10207G>A		intron_variant			NP_001230361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000398919.6	c.-149-10207G>A		intron_variant		1		ENSP00000381891	A1
ERG	ENST00000468474.5	n.38-10207G>A		intron_variant, non_coding_transcript_variant		1
ERG	ENST00000485493.1	n.38-10207G>A		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.146

Gnomad4 ASJ AF: 0.150

Gnomad4 EAS AF: 0.290

Gnomad4 SAS AF: 0.253

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.145

Alfa AF: 0.171 Hom.: 3998

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17194186; hg19: chr21-39967076; COSMIC: COSV67395850;