chr21-38398442-T-C

Variant names:

• chr21-38398442-T-C
• rs2836370
• NM_182918.4:c.745+2132A>G

Variant summary

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

The NM_182918.4(ERG):​c.745+2132A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 152,084 control chromosomes in the GnomAD database, including 12,741 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 0.39 (12741 hom., cov: 32)
• Consequence: ERG NM_182918.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.165
• Publications: 5 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.476 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.745+2132A>G		intron	N/A	NP_891548.1	P11308-4
	ERG	NM_001136154.1		c.766+2132A>G		intron	N/A	NP_001129626.1	P11308-3
	ERG	NM_001243428.1		c.766+2132A>G		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.745+2132A>G		intron	N/A	ENSP00000288319.7	P11308-4
	ERG	ENST00000398919.6	TSL:1	c.766+2132A>G		intron	N/A	ENSP00000381891.2	P11308-3
	ERG	ENST00000398905.5	TSL:1	c.673+4115A>G		intron	N/A	ENSP00000381877.1	B5MDW0

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58840 AN: 151966 Hom.: 12745 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.385

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

GnomAD4 genome AF: 0.387 AC: 58832 AN: 152084 Hom.: 12741 Cov.: 32 AF XY: 0.393 AC XY: 29219 AN XY: 74338

African (AFR) AF: 0.195 AC: 8075 AN: 41502

American (AMR) AF: 0.318 AC: 4854 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 1486 AN: 3470

East Asian (EAS) AF: 0.401 AC: 2070 AN: 5160

South Asian (SAS) AF: 0.401 AC: 1930 AN: 4814

European-Finnish (FIN) AF: 0.610 AC: 6441 AN: 10566

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.480 AC: 32645 AN: 67986

Other (OTH) AF: 0.381 AC: 805 AN: 2112

Alfa AF: 0.415 Hom.: 23923

Bravo AF: 0.358

Asia WGS AF: 0.365 AC: 1266 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.9
DANN	Benign	0.65
PhyloP100		-0.17
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: rs2836370; hg19: chr21-39770364;