rs464980

Variant names:

• chr21-38643867-T-A
• rs464980
• ENST00000398919.6:c.-150+16655A>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.-150+17791A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 152,050 control chromosomes in the GnomAD database, including 20,297 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 0.51 (20297 hom., cov: 33)
• Consequence: ERG NM_001136154.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.247
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.564 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.-150+17791A>T		intron	N/A	NP_001129626.1
	ERG	NM_001243428.1		c.-150+16655A>T		intron	N/A	NP_001230357.1
	ERG	NM_004449.4		c.-150+17791A>T		intron	N/A	NP_004440.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	ENST00000398919.6	TSL:1	c.-150+16655A>T		intron	N/A	ENSP00000381891.2
	ERG	ENST00000468474.5	TSL:1	n.37+17791A>T		intron	N/A
	ERG	ENST00000485493.1	TSL:1	n.37+17791A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77960 AN: 151932 Hom.: 20281 Cov.: 33

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.539

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

GnomAD4 genome AF: 0.513 AC: 78015 AN: 152050 Hom.: 20297 Cov.: 33 AF XY: 0.514 AC XY: 38193 AN XY: 74332

African (AFR) AF: 0.441 AC: 18296 AN: 41450

American (AMR) AF: 0.574 AC: 8772 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2242 AN: 3466

East Asian (EAS) AF: 0.438 AC: 2261 AN: 5160

South Asian (SAS) AF: 0.563 AC: 2711 AN: 4816

European-Finnish (FIN) AF: 0.483 AC: 5112 AN: 10580

Middle Eastern (MID) AF: 0.630 AC: 184 AN: 292

European-Non Finnish (NFE) AF: 0.539 AC: 36653 AN: 67984

Other (OTH) AF: 0.541 AC: 1143 AN: 2114

Alfa AF: 0.509 Hom.: 2470

Bravo AF: 0.517

Asia WGS AF: 0.497 AC: 1726 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	2.5
DANN	Benign	0.59
PhyloP100		-0.25
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: rs464980; hg19: chr21-40015791;