21-38604805-T-C

Variant names:

• chr21-38604805-T-C
• rs2836566
• ENST00000398919.6:c.-149-19860A>G

Variant summary

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

The ENST00000398919.6(ERG):​c.-149-19860A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 152,202 control chromosomes in the GnomAD database, including 2,385 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 0.18 (2385 hom., cov: 33)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.67
• 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=-0.94).
• 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.-149-19860A>G		intron_variant	Intron 1 of 11		NP_001129626.1
ERG	NM_001243428.1	c.-149-19860A>G		intron_variant	Intron 1 of 11		NP_001230357.1
ERG	NM_004449.4	c.-149-19860A>G		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.-149-19860A>G		intron_variant	Intron 1 of 11	1		ENSP00000381891.2
ERG	ENST00000468474.5	n.38-19860A>G		intron_variant	Intron 1 of 7	1
ERG	ENST00000485493.1	n.38-19860A>G		intron_variant	Intron 1 of 4	1

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26607 AN: 152084 Hom.: 2379 Cov.: 33

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.159

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

GnomAD4 genome AF: 0.175 AC: 26638 AN: 152202 Hom.: 2385 Cov.: 33 AF XY: 0.177 AC XY: 13130 AN XY: 74390

African (AFR) AF: 0.160 AC: 6660 AN: 41546

American (AMR) AF: 0.149 AC: 2279 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 525 AN: 3468

East Asian (EAS) AF: 0.291 AC: 1505 AN: 5164

South Asian (SAS) AF: 0.247 AC: 1188 AN: 4814

European-Finnish (FIN) AF: 0.189 AC: 2000 AN: 10582

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12039 AN: 68008

Other (OTH) AF: 0.158 AC: 335 AN: 2114

Alfa AF: 0.177 Hom.: 307

Bravo AF: 0.171

Asia WGS AF: 0.241 AC: 842 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.0060
DANN	Benign	0.65
PhyloP100		-2.7
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: rs2836566; hg19: chr21-39976729;