21-38645522-G-T

Variant names:

• chr21-38645522-G-T
• rs9981408
• ENST00000398919.6:c.-150+15000C>A

Variant summary

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

The ENST00000398919.6(ERG):​c.-150+15000C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 152,038 control chromosomes in the GnomAD database, including 4,205 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 0.23 (4205 hom., cov: 32)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 5 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.282 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.-150+16136C>A		intron	N/A	NP_001129626.1
	ERG	NM_001243428.1		c.-150+15000C>A		intron	N/A	NP_001230357.1
	ERG	NM_004449.4		c.-150+16136C>A		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.-150+15000C>A		intron	N/A	ENSP00000381891.2
	ERG	ENST00000468474.5	TSL:1	n.37+16136C>A		intron	N/A
	ERG	ENST00000485493.1	TSL:1	n.37+16136C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35339 AN: 151920 Hom.: 4196 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.195

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

GnomAD4 genome AF: 0.233 AC: 35367 AN: 152038 Hom.: 4205 Cov.: 32 AF XY: 0.231 AC XY: 17184 AN XY: 74302

African (AFR) AF: 0.261 AC: 10832 AN: 41460

American (AMR) AF: 0.179 AC: 2738 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 600 AN: 3472

East Asian (EAS) AF: 0.294 AC: 1516 AN: 5156

South Asian (SAS) AF: 0.228 AC: 1102 AN: 4824

European-Finnish (FIN) AF: 0.240 AC: 2530 AN: 10556

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15463 AN: 67986

Other (OTH) AF: 0.194 AC: 408 AN: 2102

Alfa AF: 0.246 Hom.: 576

Bravo AF: 0.229

Asia WGS AF: 0.245 AC: 852 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.18
DANN	Benign	0.74
PhyloP100		-1.1
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: rs9981408; hg19: chr21-40017446;