rs2836391

Variant names:

• chr21-38433875-G-A
• rs2836391
• NM_182918.4:c.237-10314C>T

Variant summary

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

The NM_182918.4(ERG):​c.237-10314C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 152,100 control chromosomes in the GnomAD database, including 3,122 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 0.20 (3122 hom., cov: 32)
• Consequence: ERG NM_182918.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.30
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182918.4. 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_182918.4	MANE Select	c.237-10314C>T		intron	N/A	NP_891548.1	P11308-4
	ERG	NM_001136154.1		c.258-10314C>T		intron	N/A	NP_001129626.1	P11308-3
	ERG	NM_001243428.1		c.258-10314C>T		intron	N/A	NP_001230357.1	P11308-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	ENST00000288319.12	TSL:1 MANE Select	c.237-10314C>T		intron	N/A	ENSP00000288319.7	P11308-4
	ERG	ENST00000398919.6	TSL:1	c.258-10314C>T		intron	N/A	ENSP00000381891.2	P11308-3
	ERG	ENST00000398905.5	TSL:1	c.237-10314C>T		intron	N/A	ENSP00000381877.1	B5MDW0

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29873 AN: 151982 Hom.: 3114 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.204

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

GnomAD4 genome AF: 0.197 AC: 29914 AN: 152100 Hom.: 3122 Cov.: 32 AF XY: 0.196 AC XY: 14541 AN XY: 74364

African (AFR) AF: 0.163 AC: 6773 AN: 41478

American (AMR) AF: 0.178 AC: 2722 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 989 AN: 3472

East Asian (EAS) AF: 0.206 AC: 1065 AN: 5174

South Asian (SAS) AF: 0.297 AC: 1426 AN: 4802

European-Finnish (FIN) AF: 0.155 AC: 1643 AN: 10580

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14433 AN: 67990

Other (OTH) AF: 0.207 AC: 437 AN: 2110

Alfa AF: 0.189 Hom.: 539

Bravo AF: 0.198

Asia WGS AF: 0.258 AC: 900 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.074
DANN	Benign	0.70
PhyloP100		-2.3
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: rs2836391; hg19: chr21-39805797;