rs2836505

Positions:

• chr21-38546629-G-A
• chr21-38546629-G-C
• chr21-38546629-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001136154.1(ERG):​c.39+29033C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 152,070 control chromosomes in the GnomAD database, including 2,737 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 0.18 (2737 hom., cov: 32)
• Consequence: ERG NM_001136154.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERG	NM_001136154.1	c.39+29033C>T		intron_variant			NP_001129626.1
ERG	NM_001243428.1	c.39+29033C>T		intron_variant			NP_001230357.1
ERG	NM_004449.4	c.39+29033C>T		intron_variant			NP_004440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000398919.6	c.39+29033C>T		intron_variant		1		ENSP00000381891.2
ERG	ENST00000468474.5	n.225+29033C>T		intron_variant		1
ERG	ENST00000485493.1	n.225+29033C>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27610 AN: 151952 Hom.: 2730 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.171

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

GnomAD4 genome AF: 0.182 AC: 27643 AN: 152070 Hom.: 2737 Cov.: 32 AF XY: 0.186 AC XY: 13824 AN XY: 74336

Gnomad4 AFR AF: 0.240

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.174

Gnomad4 EAS AF: 0.332

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.176

Alfa AF: 0.138 Hom.: 3146

Bravo AF: 0.178

Asia WGS AF: 0.275 AC: 956 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.054
DANN	Benign	0.75

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2836505; hg19: chr21-39918553;