21-38638860-C-G

Variant names:

• chr21-38638860-C-G
• rs2836580
• ENST00000398919.6:c.-150+21662G>C

Variant summary

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

The ENST00000398919.6(ERG):​c.-150+21662G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,078 control chromosomes in the GnomAD database, including 2,843 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 0.19 (2843 hom., cov: 32)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28
• 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 (EAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_001136154.1	c.-150+22798G>C		intron_variant	Intron 1 of 11		NP_001129626.1
ERG	NM_001243428.1	c.-150+21662G>C		intron_variant	Intron 1 of 11		NP_001230357.1
ERG	NM_004449.4	c.-150+22798G>C		intron_variant	Intron 1 of 10		NP_004440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000398919.6	c.-150+21662G>C		intron_variant	Intron 1 of 11	1		ENSP00000381891.2
ERG	ENST00000468474.5	n.37+22798G>C		intron_variant	Intron 1 of 7	1
ERG	ENST00000485493.1	n.37+22798G>C		intron_variant	Intron 1 of 4	1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28249 AN: 151960 Hom.: 2832 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.169

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

GnomAD4 genome AF: 0.186 AC: 28294 AN: 152078 Hom.: 2843 Cov.: 32 AF XY: 0.184 AC XY: 13714 AN XY: 74346

African (AFR) AF: 0.233 AC: 9661 AN: 41456

American (AMR) AF: 0.153 AC: 2345 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 545 AN: 3468

East Asian (EAS) AF: 0.292 AC: 1503 AN: 5156

South Asian (SAS) AF: 0.236 AC: 1137 AN: 4814

European-Finnish (FIN) AF: 0.144 AC: 1526 AN: 10600

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11111 AN: 67978

Other (OTH) AF: 0.169 AC: 357 AN: 2114

Alfa AF: 0.0805 Hom.: 114

Bravo AF: 0.189

Asia WGS AF: 0.258 AC: 900 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	2.1
DANN	Benign	0.81
PhyloP100		1.3
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: rs2836580; hg19: chr21-40010784;