chr21-38579624-C-A

Variant names:

• chr21-38579624-C-A
• rs2836537
• ENST00000398919.6:c.-47-3877G>T

Variant summary

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

The ENST00000398919.6(ERG):​c.-47-3877G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 151,960 control chromosomes in the GnomAD database, including 15,560 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 0.41 (15560 hom., cov: 31)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.590
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_001136154.1	c.-47-3877G>T		intron_variant	Intron 2 of 11		NP_001129626.1
ERG	NM_001243428.1	c.-47-3877G>T		intron_variant	Intron 2 of 11		NP_001230357.1
ERG	NM_004449.4	c.-47-3877G>T		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.-47-3877G>T		intron_variant	Intron 2 of 11	1		ENSP00000381891.2
ERG	ENST00000468474.5	n.140-3877G>T		intron_variant	Intron 2 of 7	1
ERG	ENST00000485493.1	n.140-3877G>T		intron_variant	Intron 2 of 4	1

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61772 AN: 151844 Hom.: 15570 Cov.: 31

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.633

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.460

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

GnomAD4 genome AF: 0.406 AC: 61744 AN: 151960 Hom.: 15560 Cov.: 31 AF XY: 0.404 AC XY: 29967 AN XY: 74250

African (AFR) AF: 0.104 AC: 4298 AN: 41490

American (AMR) AF: 0.425 AC: 6493 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 2199 AN: 3472

East Asian (EAS) AF: 0.415 AC: 2140 AN: 5154

South Asian (SAS) AF: 0.408 AC: 1959 AN: 4798

European-Finnish (FIN) AF: 0.488 AC: 5140 AN: 10542

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37930 AN: 67920

Other (OTH) AF: 0.456 AC: 960 AN: 2106

Alfa AF: 0.501 Hom.: 13861

Bravo AF: 0.389

Asia WGS AF: 0.391 AC: 1359 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.59
DANN	Benign	0.68
PhyloP100		-0.59
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: rs2836537; hg19: chr21-39951548;