ENST00000398919.6:c.39+9174G>T

Variant names:

• chr21-38566488-C-A
• rs2836518
• ENST00000398919.6:c.39+9174G>T

Variant summary

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

The ENST00000398919.6(ERG):​c.39+9174G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.863 in 152,174 control chromosomes in the GnomAD database, including 56,788 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 0.86 (56788 hom., cov: 31)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 3 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=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_001136154.1	c.39+9174G>T		intron_variant	Intron 3 of 11		NP_001129626.1
ERG	NM_001243428.1	c.39+9174G>T		intron_variant	Intron 3 of 11		NP_001230357.1
ERG	NM_004449.4	c.39+9174G>T		intron_variant	Intron 3 of 10		NP_004440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000398919.6	c.39+9174G>T		intron_variant	Intron 3 of 11	1		ENSP00000381891.2
ERG	ENST00000468474.5	n.225+9174G>T		intron_variant	Intron 3 of 7	1
ERG	ENST00000485493.1	n.225+9174G>T		intron_variant	Intron 3 of 4	1

Frequencies

GnomAD3 genomes AF: 0.863 AC: 131150 AN: 152056 Hom.: 56734 Cov.: 31

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.957

Gnomad AMR AF: 0.809

Gnomad ASJ AF: 0.932

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.916

Gnomad FIN AF: 0.895

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.858

Gnomad OTH AF: 0.859

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

GnomAD4 genome AF: 0.863 AC: 131266 AN: 152174 Hom.: 56788 Cov.: 31 AF XY: 0.863 AC XY: 64226 AN XY: 74382

African (AFR) AF: 0.898 AC: 37252 AN: 41504

American (AMR) AF: 0.809 AC: 12362 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.932 AC: 3235 AN: 3472

East Asian (EAS) AF: 0.622 AC: 3207 AN: 5154

South Asian (SAS) AF: 0.916 AC: 4414 AN: 4820

European-Finnish (FIN) AF: 0.895 AC: 9494 AN: 10610

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

European-Non Finnish (NFE) AF: 0.858 AC: 58363 AN: 68006

Other (OTH) AF: 0.857 AC: 1811 AN: 2112

Alfa AF: 0.863 Hom.: 92554

Bravo AF: 0.855

Asia WGS AF: 0.790 AC: 2748 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.23
DANN	Benign	0.36
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: rs2836518; hg19: chr21-39938412;