chr21-38577066-A-G

Variant names:

• chr21-38577066-A-G
• rs2836531
• ENST00000398919.6:c.-47-1319T>C

Variant summary

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

The ENST00000398919.6(ERG):​c.-47-1319T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 152,096 control chromosomes in the GnomAD database, including 28,417 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 0.58 (28417 hom., cov: 33)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0420
• Publications: 2 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000398919.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	NM_001136154.1		c.-47-1319T>C		intron	N/A	NP_001129626.1
	ERG	NM_001243428.1		c.-47-1319T>C		intron	N/A	NP_001230357.1
	ERG	NM_004449.4		c.-47-1319T>C		intron	N/A	NP_004440.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	ENST00000398919.6	TSL:1	c.-47-1319T>C		intron	N/A	ENSP00000381891.2
	ERG	ENST00000468474.5	TSL:1	n.140-1319T>C		intron	N/A
	ERG	ENST00000485493.1	TSL:1	n.140-1319T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88743 AN: 151978 Hom.: 28344 Cov.: 33

Gnomad AFR AF: 0.854

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.585

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.540

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

GnomAD4 genome AF: 0.584 AC: 88883 AN: 152096 Hom.: 28417 Cov.: 33 AF XY: 0.587 AC XY: 43635 AN XY: 74332

African (AFR) AF: 0.854 AC: 35448 AN: 41496

American (AMR) AF: 0.578 AC: 8835 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 1267 AN: 3464

East Asian (EAS) AF: 0.563 AC: 2906 AN: 5162

South Asian (SAS) AF: 0.586 AC: 2826 AN: 4824

European-Finnish (FIN) AF: 0.512 AC: 5415 AN: 10566

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.448 AC: 30457 AN: 67982

Other (OTH) AF: 0.545 AC: 1149 AN: 2110

Alfa AF: 0.559 Hom.: 5032

Bravo AF: 0.600

Asia WGS AF: 0.606 AC: 2107 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.41
PhyloP100		-0.042
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: rs2836531; hg19: chr21-39948990;