rs2836439

Variant names:

• chr21-38493226-C-T
• rs2836439
• NM_182918.4:c.18+5137G>A

Variant summary

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

The NM_182918.4(ERG):​c.18+5137G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 152,092 control chromosomes in the GnomAD database, including 2,048 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 (2048 hom., cov: 33)
• Consequence: ERG NM_182918.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.76
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_182918.4	c.18+5137G>A		intron_variant	Intron 1 of 9	ENST00000288319.12	NP_891548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000288319.12	c.18+5137G>A		intron_variant	Intron 1 of 9	1	NM_182918.4	ENSP00000288319.7

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24542 AN: 151974 Hom.: 2047 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.164

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

GnomAD4 genome AF: 0.161 AC: 24554 AN: 152092 Hom.: 2048 Cov.: 33 AF XY: 0.161 AC XY: 11987 AN XY: 74338

African (AFR) AF: 0.126 AC: 5217 AN: 41492

American (AMR) AF: 0.151 AC: 2313 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 706 AN: 3472

East Asian (EAS) AF: 0.187 AC: 964 AN: 5166

South Asian (SAS) AF: 0.127 AC: 609 AN: 4812

European-Finnish (FIN) AF: 0.174 AC: 1837 AN: 10560

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12354 AN: 67992

Other (OTH) AF: 0.164 AC: 345 AN: 2108

Alfa AF: 0.174 Hom.: 9857

Bravo AF: 0.160

Asia WGS AF: 0.138 AC: 484 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.040
DANN	Benign	0.38
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2836439; hg19: chr21-39865150;