rs2836565

Variant names:

• chr21-38604777-G-A
• rs2836565
• ENST00000398919.6:c.-149-19832C>T

Variant summary

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

The NM_001136154.1(ERG):​c.-149-19832C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 152,172 control chromosomes in the GnomAD database, including 3,629 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 0.20 (3629 hom., cov: 33)
• Consequence: ERG NM_001136154.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.232
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136154.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	NM_001136154.1		c.-149-19832C>T		intron	N/A	NP_001129626.1	P11308-3
	ERG	NM_001243428.1		c.-149-19832C>T		intron	N/A	NP_001230357.1	P11308-3
	ERG	NM_004449.4		c.-149-19832C>T		intron	N/A	NP_004440.1	P11308-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	ENST00000398919.6	TSL:1	c.-149-19832C>T		intron	N/A	ENSP00000381891.2	P11308-3
	ERG	ENST00000468474.5	TSL:1	n.38-19832C>T		intron	N/A
	ERG	ENST00000485493.1	TSL:1	n.38-19832C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30944 AN: 152054 Hom.: 3630 Cov.: 33

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.0439

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.220

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

GnomAD4 genome AF: 0.203 AC: 30944 AN: 152172 Hom.: 3629 Cov.: 33 AF XY: 0.201 AC XY: 14979 AN XY: 74396

African (AFR) AF: 0.112 AC: 4672 AN: 41534

American (AMR) AF: 0.158 AC: 2412 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 911 AN: 3470

East Asian (EAS) AF: 0.0432 AC: 224 AN: 5180

South Asian (SAS) AF: 0.152 AC: 732 AN: 4816

European-Finnish (FIN) AF: 0.267 AC: 2826 AN: 10580

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.271 AC: 18396 AN: 67976

Other (OTH) AF: 0.218 AC: 461 AN: 2114

Alfa AF: 0.248 Hom.: 21099

Bravo AF: 0.192

Asia WGS AF: 0.105 AC: 368 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.7
DANN	Benign	0.55
PhyloP100		0.23
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: rs2836565; hg19: chr21-39976701;