21-38545256-C-T

Variant names:

• chr21-38545256-C-T
• rs2836502
• ENST00000398919.6:c.39+30406G>A

Variant summary

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

The ENST00000398919.6(ERG):​c.39+30406G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 151,936 control chromosomes in the GnomAD database, including 20,706 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 0.51 (20706 hom., cov: 32)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.31
• Publications: 1 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_001136154.1	c.39+30406G>A		intron_variant	Intron 3 of 11		NP_001129626.1
ERG	NM_001243428.1	c.39+30406G>A		intron_variant	Intron 3 of 11		NP_001230357.1
ERG	NM_004449.4	c.39+30406G>A		intron_variant	Intron 3 of 10		NP_004440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000398919.6	c.39+30406G>A		intron_variant	Intron 3 of 11	1		ENSP00000381891.2
ERG	ENST00000468474.5	n.225+30406G>A		intron_variant	Intron 3 of 7	1
ERG	ENST00000485493.1	n.225+30406G>A		intron_variant	Intron 3 of 4	1

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76789 AN: 151818 Hom.: 20713 Cov.: 32

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.839

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.667

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.537

Gnomad MID AF: 0.561

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.531

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

GnomAD4 genome AF: 0.506 AC: 76807 AN: 151936 Hom.: 20706 Cov.: 32 AF XY: 0.498 AC XY: 36989 AN XY: 74224

African (AFR) AF: 0.359 AC: 14858 AN: 41412

American (AMR) AF: 0.428 AC: 6533 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 2313 AN: 3466

East Asian (EAS) AF: 0.157 AC: 811 AN: 5166

South Asian (SAS) AF: 0.456 AC: 2193 AN: 4812

European-Finnish (FIN) AF: 0.537 AC: 5654 AN: 10538

Middle Eastern (MID) AF: 0.565 AC: 165 AN: 292

European-Non Finnish (NFE) AF: 0.624 AC: 42407 AN: 67960

Other (OTH) AF: 0.527 AC: 1108 AN: 2102

Alfa AF: 0.463 Hom.: 2324

Bravo AF: 0.490

Asia WGS AF: 0.322 AC: 1122 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.23
DANN	Benign	0.33
PhyloP100		-2.3
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: rs2836502; hg19: chr21-39917180; COSMIC: COSV67368283;