rs2836542

Variant names:

• chr21-38583514-A-C
• rs2836542
• ENST00000398919.6:c.-48+1330T>G

Variant summary

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

The ENST00000398919.6(ERG):​c.-48+1330T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 152,064 control chromosomes in the GnomAD database, including 21,809 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 0.50 (21809 hom., cov: 32)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.73
• 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=-1.05).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_001136154.1	c.-48+1330T>G		intron_variant	Intron 2 of 11		NP_001129626.1
ERG	NM_001243428.1	c.-48+1330T>G		intron_variant	Intron 2 of 11		NP_001230357.1
ERG	NM_004449.4	c.-48+1330T>G		intron_variant	Intron 2 of 10		NP_004440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000398919.6	c.-48+1330T>G		intron_variant	Intron 2 of 11	1		ENSP00000381891.2
ERG	ENST00000468474.5	n.139+1330T>G		intron_variant	Intron 2 of 7	1
ERG	ENST00000485493.1	n.139+1330T>G		intron_variant	Intron 2 of 4	1

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76130 AN: 151944 Hom.: 21818 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.554

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.531

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

GnomAD4 genome AF: 0.501 AC: 76133 AN: 152064 Hom.: 21809 Cov.: 32 AF XY: 0.501 AC XY: 37251 AN XY: 74306

African (AFR) AF: 0.210 AC: 8731 AN: 41488

American (AMR) AF: 0.524 AC: 8004 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2447 AN: 3470

East Asian (EAS) AF: 0.543 AC: 2808 AN: 5170

South Asian (SAS) AF: 0.551 AC: 2657 AN: 4820

European-Finnish (FIN) AF: 0.600 AC: 6330 AN: 10546

Middle Eastern (MID) AF: 0.555 AC: 162 AN: 292

European-Non Finnish (NFE) AF: 0.638 AC: 43377 AN: 67982

Other (OTH) AF: 0.528 AC: 1116 AN: 2112

Alfa AF: 0.597 Hom.: 46278

Bravo AF: 0.478

Asia WGS AF: 0.533 AC: 1854 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.62
DANN	Benign	0.55
PhyloP100		-1.7
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: rs2836542; hg19: chr21-39955438;