21-38614321-T-C

Variant names:

• chr21-38614321-T-C
• rs460574
• ENST00000398919.6:c.-149-29376A>G

Variant summary

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

The ENST00000398919.6(ERG):​c.-149-29376A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 152,048 control chromosomes in the GnomAD database, including 29,767 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 0.62 (29767 hom., cov: 31)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.12
• Publications: 9 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_001136154.1	c.-149-29376A>G		intron_variant	Intron 1 of 11		NP_001129626.1
ERG	NM_001243428.1	c.-149-29376A>G		intron_variant	Intron 1 of 11		NP_001230357.1
ERG	NM_004449.4	c.-149-29376A>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.-149-29376A>G		intron_variant	Intron 1 of 11	1		ENSP00000381891.2
ERG	ENST00000468474.5	n.38-29376A>G		intron_variant	Intron 1 of 7	1
ERG	ENST00000485493.1	n.38-29376A>G		intron_variant	Intron 1 of 4	1

Frequencies

GnomAD3 genomes AF: 0.621 AC: 94389 AN: 151930 Hom.: 29714 Cov.: 31

Gnomad AFR AF: 0.699

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.626

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.598

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

GnomAD4 genome AF: 0.622 AC: 94501 AN: 152048 Hom.: 29767 Cov.: 31 AF XY: 0.625 AC XY: 46487 AN XY: 74344

African (AFR) AF: 0.700 AC: 29013 AN: 41466

American (AMR) AF: 0.612 AC: 9357 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1753 AN: 3470

East Asian (EAS) AF: 0.736 AC: 3802 AN: 5164

South Asian (SAS) AF: 0.626 AC: 3018 AN: 4820

European-Finnish (FIN) AF: 0.633 AC: 6693 AN: 10576

Middle Eastern (MID) AF: 0.455 AC: 133 AN: 292

European-Non Finnish (NFE) AF: 0.575 AC: 39066 AN: 67958

Other (OTH) AF: 0.599 AC: 1266 AN: 2112

Alfa AF: 0.592 Hom.: 26306

Bravo AF: 0.623

Asia WGS AF: 0.697 AC: 2427 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.51
DANN	Benign	0.53
PhyloP100		-2.1
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: rs460574; hg19: chr21-39986245; COSMIC: COSV67394999;