rs3761366

Variant names:

• chr21-38576998-G-A
• rs3761366
• ENST00000398919.6:c.-47-1251C>T

Variant summary

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

The ENST00000398919.6(ERG):​c.-47-1251C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.079 in 152,174 control chromosomes in the GnomAD database, including 510 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 0.079 (510 hom., cov: 32)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.304
• Publications: 4 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000398919.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	NM_001136154.1		c.-47-1251C>T		intron	N/A	NP_001129626.1
	ERG	NM_001243428.1		c.-47-1251C>T		intron	N/A	NP_001230357.1
	ERG	NM_004449.4		c.-47-1251C>T		intron	N/A	NP_004440.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	ENST00000398919.6	TSL:1	c.-47-1251C>T		intron	N/A	ENSP00000381891.2
	ERG	ENST00000468474.5	TSL:1	n.140-1251C>T		intron	N/A
	ERG	ENST00000485493.1	TSL:1	n.140-1251C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0789 AC: 12004 AN: 152056 Hom.: 508 Cov.: 32

Gnomad AFR AF: 0.0682

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0764

Gnomad ASJ AF: 0.0608

Gnomad EAS AF: 0.0869

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.0562

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0836

Gnomad OTH AF: 0.0914

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

GnomAD4 genome AF: 0.0790 AC: 12021 AN: 152174 Hom.: 510 Cov.: 32 AF XY: 0.0784 AC XY: 5836 AN XY: 74410

African (AFR) AF: 0.0681 AC: 2828 AN: 41532

American (AMR) AF: 0.0764 AC: 1168 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 211 AN: 3468

East Asian (EAS) AF: 0.0869 AC: 449 AN: 5168

South Asian (SAS) AF: 0.154 AC: 743 AN: 4822

European-Finnish (FIN) AF: 0.0562 AC: 596 AN: 10598

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0836 AC: 5680 AN: 67978

Other (OTH) AF: 0.0966 AC: 204 AN: 2112

Alfa AF: 0.0824 Hom.: 344

Bravo AF: 0.0803

Asia WGS AF: 0.146 AC: 506 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.64
DANN	Benign	0.26
PhyloP100		-0.30
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: rs3761366; hg19: chr21-39948922;