21-38404640-T-C

Variant names:

• chr21-38404640-T-C
• rs1892570
• NM_182918.4:c.389-931A>G

Variant summary

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

The NM_182918.4(ERG):​c.389-931A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.84 in 152,098 control chromosomes in the GnomAD database, including 54,882 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 0.84 (54882 hom., cov: 31)
• Consequence: ERG NM_182918.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0930
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_182918.4	c.389-931A>G		intron_variant	Intron 3 of 9	ENST00000288319.12	NP_891548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000288319.12	c.389-931A>G		intron_variant	Intron 3 of 9	1	NM_182918.4	ENSP00000288319.7

Frequencies

GnomAD3 genomes AF: 0.840 AC: 127698 AN: 151980 Hom.: 54856 Cov.: 31

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.931

Gnomad EAS AF: 0.816

Gnomad SAS AF: 0.925

Gnomad FIN AF: 0.937

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.935

Gnomad OTH AF: 0.838

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

GnomAD4 genome AF: 0.840 AC: 127769 AN: 152098 Hom.: 54882 Cov.: 31 AF XY: 0.842 AC XY: 62634 AN XY: 74376

African (AFR) AF: 0.645 AC: 26738 AN: 41430

American (AMR) AF: 0.828 AC: 12658 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.931 AC: 3227 AN: 3468

East Asian (EAS) AF: 0.816 AC: 4224 AN: 5176

South Asian (SAS) AF: 0.925 AC: 4460 AN: 4820

European-Finnish (FIN) AF: 0.937 AC: 9937 AN: 10602

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.935 AC: 63602 AN: 68006

Other (OTH) AF: 0.836 AC: 1763 AN: 2108

Alfa AF: 0.907 Hom.: 104526

Bravo AF: 0.823

Asia WGS AF: 0.835 AC: 2903 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.5
DANN	Benign	0.64
PhyloP100		-0.093
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1892570; hg19: chr21-39776562;