rs717231

Variant names:

• chr21-38579238-C-A
• rs717231
• ENST00000398919.6:c.-47-3491G>T

Variant summary

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

The NM_001136154.1(ERG):​c.-47-3491G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 152,004 control chromosomes in the GnomAD database, including 5,886 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 0.27 (5886 hom., cov: 32)
• Consequence: ERG NM_001136154.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0180
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136154.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	NM_001136154.1		c.-47-3491G>T		intron	N/A	NP_001129626.1	P11308-3
	ERG	NM_001243428.1		c.-47-3491G>T		intron	N/A	NP_001230357.1	P11308-3
	ERG	NM_004449.4		c.-47-3491G>T		intron	N/A	NP_004440.1	P11308-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	ENST00000398919.6	TSL:1	c.-47-3491G>T		intron	N/A	ENSP00000381891.2	P11308-3
	ERG	ENST00000468474.5	TSL:1	n.140-3491G>T		intron	N/A
	ERG	ENST00000485493.1	TSL:1	n.140-3491G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41371 AN: 151888 Hom.: 5864 Cov.: 32

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.251

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

GnomAD4 genome AF: 0.273 AC: 41455 AN: 152004 Hom.: 5886 Cov.: 32 AF XY: 0.278 AC XY: 20620 AN XY: 74302

African (AFR) AF: 0.289 AC: 11995 AN: 41478

American (AMR) AF: 0.353 AC: 5388 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 621 AN: 3470

East Asian (EAS) AF: 0.311 AC: 1600 AN: 5150

South Asian (SAS) AF: 0.376 AC: 1810 AN: 4820

European-Finnish (FIN) AF: 0.281 AC: 2962 AN: 10544

Middle Eastern (MID) AF: 0.247 AC: 72 AN: 292

European-Non Finnish (NFE) AF: 0.239 AC: 16214 AN: 67960

Other (OTH) AF: 0.257 AC: 541 AN: 2104

Alfa AF: 0.246 Hom.: 7767

Bravo AF: 0.278

Asia WGS AF: 0.378 AC: 1313 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.5
DANN	Benign	0.80
PhyloP100		0.018
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: rs717231; hg19: chr21-39951162;