chr21-38433953-A-G

Variant names:

• chr21-38433953-A-G
• rs2836392
• NM_182918.4:c.237-10392T>C

Variant summary

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

The NM_182918.4(ERG):​c.237-10392T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.788 in 152,068 control chromosomes in the GnomAD database, including 47,368 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 0.79 (47368 hom., cov: 31)
• Consequence: ERG NM_182918.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51
• Publications: 8 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 (AFR) allele frequency at 95% confidence interval = 0.826 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	NM_182918.4	MANE Select	c.237-10392T>C		intron	N/A	NP_891548.1
	ERG	NM_001136154.1		c.258-10392T>C		intron	N/A	NP_001129626.1
	ERG	NM_001243428.1		c.258-10392T>C		intron	N/A	NP_001230357.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	ENST00000288319.12	TSL:1 MANE Select	c.237-10392T>C		intron	N/A	ENSP00000288319.7
	ERG	ENST00000398919.6	TSL:1	c.258-10392T>C		intron	N/A	ENSP00000381891.2
	ERG	ENST00000398905.5	TSL:1	c.237-10392T>C		intron	N/A	ENSP00000381877.1

Frequencies

GnomAD3 genomes AF: 0.788 AC: 119687 AN: 151950 Hom.: 47341 Cov.: 31

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.803

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.793

Gnomad SAS AF: 0.698

Gnomad FIN AF: 0.830

Gnomad MID AF: 0.755

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.778

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

GnomAD4 genome AF: 0.788 AC: 119766 AN: 152068 Hom.: 47368 Cov.: 31 AF XY: 0.789 AC XY: 58645 AN XY: 74306

African (AFR) AF: 0.833 AC: 34567 AN: 41478

American (AMR) AF: 0.802 AC: 12258 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 2380 AN: 3472

East Asian (EAS) AF: 0.792 AC: 4094 AN: 5168

South Asian (SAS) AF: 0.699 AC: 3360 AN: 4810

European-Finnish (FIN) AF: 0.830 AC: 8770 AN: 10570

Middle Eastern (MID) AF: 0.753 AC: 220 AN: 292

European-Non Finnish (NFE) AF: 0.764 AC: 51934 AN: 67976

Other (OTH) AF: 0.775 AC: 1637 AN: 2112

Alfa AF: 0.765 Hom.: 75360

Bravo AF: 0.787

Asia WGS AF: 0.737 AC: 2563 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.60
DANN	Benign	0.29
PhyloP100		-1.5
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: rs2836392; hg19: chr21-39805875;