rs9982370

Variant names:

• chr21-38493931-C-T
• rs9982370
• NM_182918.4:c.18+4432G>A

Variant summary

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

The NM_182918.4(ERG):​c.18+4432G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 152,096 control chromosomes in the GnomAD database, including 3,772 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 0.22 (3772 hom., cov: 33)
• Consequence: ERG NM_182918.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 6 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_182918.4	c.18+4432G>A		intron_variant	Intron 1 of 9	ENST00000288319.12	NP_891548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000288319.12	c.18+4432G>A		intron_variant	Intron 1 of 9	1	NM_182918.4	ENSP00000288319.7

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33683 AN: 151978 Hom.: 3768 Cov.: 33

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.218

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

GnomAD4 genome AF: 0.222 AC: 33709 AN: 152096 Hom.: 3772 Cov.: 33 AF XY: 0.223 AC XY: 16587 AN XY: 74346

African (AFR) AF: 0.218 AC: 9059 AN: 41476

American (AMR) AF: 0.192 AC: 2939 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 807 AN: 3470

East Asian (EAS) AF: 0.180 AC: 932 AN: 5172

South Asian (SAS) AF: 0.251 AC: 1210 AN: 4820

European-Finnish (FIN) AF: 0.256 AC: 2713 AN: 10584

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15353 AN: 67962

Other (OTH) AF: 0.220 AC: 466 AN: 2116

Alfa AF: 0.221 Hom.: 1660

Bravo AF: 0.214

Asia WGS AF: 0.230 AC: 800 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.6
DANN	Benign	0.67
PhyloP100		1.0
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: rs9982370; hg19: chr21-39865855;