chr21-38577120-A-T

Variant names:

• chr21-38577120-A-T
• rs2836532
• ENST00000398919.6:c.-47-1373T>A

Variant summary

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

The ENST00000398919.6(ERG):​c.-47-1373T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 152,110 control chromosomes in the GnomAD database, including 11,745 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 0.39 (11745 hom., cov: 33)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.128
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_001136154.1	c.-47-1373T>A		intron_variant	Intron 2 of 11		NP_001129626.1
ERG	NM_001243428.1	c.-47-1373T>A		intron_variant	Intron 2 of 11		NP_001230357.1
ERG	NM_004449.4	c.-47-1373T>A		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.-47-1373T>A		intron_variant	Intron 2 of 11	1		ENSP00000381891.2
ERG	ENST00000468474.5	n.140-1373T>A		intron_variant	Intron 2 of 7	1
ERG	ENST00000485493.1	n.140-1373T>A		intron_variant	Intron 2 of 4	1

Frequencies

GnomAD3 genomes AF: 0.388 AC: 59039 AN: 151992 Hom.: 11708 Cov.: 33

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.360

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

GnomAD4 genome AF: 0.389 AC: 59136 AN: 152110 Hom.: 11745 Cov.: 33 AF XY: 0.396 AC XY: 29455 AN XY: 74374

African (AFR) AF: 0.423 AC: 17551 AN: 41484

American (AMR) AF: 0.440 AC: 6727 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 819 AN: 3472

East Asian (EAS) AF: 0.335 AC: 1733 AN: 5170

South Asian (SAS) AF: 0.453 AC: 2183 AN: 4822

European-Finnish (FIN) AF: 0.470 AC: 4969 AN: 10572

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 24028 AN: 67984

Other (OTH) AF: 0.365 AC: 770 AN: 2112

Alfa AF: 0.259 Hom.: 700

Bravo AF: 0.385

Asia WGS AF: 0.449 AC: 1560 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.46
PhyloP100		-0.13
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: rs2836532; hg19: chr21-39949044;