21-38634157-T-C

Variant names:

• chr21-38634157-T-C
• rs460214
• ENST00000398919.6:c.-150+26365A>G

Variant summary

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

The ENST00000398919.6(ERG):​c.-150+26365A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 152,130 control chromosomes in the GnomAD database, including 10,958 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 0.36 (10958 hom., cov: 33)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0750
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_001136154.1	c.-150+27501A>G		intron_variant	Intron 1 of 11		NP_001129626.1
ERG	NM_001243428.1	c.-150+26365A>G		intron_variant	Intron 1 of 11		NP_001230357.1
ERG	NM_004449.4	c.-150+27501A>G		intron_variant	Intron 1 of 10		NP_004440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000398919.6	c.-150+26365A>G		intron_variant	Intron 1 of 11	1		ENSP00000381891.2
ERG	ENST00000468474.5	n.37+27501A>G		intron_variant	Intron 1 of 7	1
ERG	ENST00000485493.1	n.37+27501A>G		intron_variant	Intron 1 of 4	1

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54640 AN: 152012 Hom.: 10926 Cov.: 33

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.318

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

GnomAD4 genome AF: 0.360 AC: 54735 AN: 152130 Hom.: 10958 Cov.: 33 AF XY: 0.367 AC XY: 27261 AN XY: 74370

African (AFR) AF: 0.477 AC: 19796 AN: 41484

American (AMR) AF: 0.417 AC: 6374 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 797 AN: 3470

East Asian (EAS) AF: 0.648 AC: 3349 AN: 5170

South Asian (SAS) AF: 0.452 AC: 2179 AN: 4824

European-Finnish (FIN) AF: 0.312 AC: 3301 AN: 10572

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18033 AN: 67994

Other (OTH) AF: 0.321 AC: 679 AN: 2112

Alfa AF: 0.286 Hom.: 8492

Bravo AF: 0.373

Asia WGS AF: 0.561 AC: 1951 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.6
DANN	Benign	0.71
PhyloP100		0.075
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: rs460214; hg19: chr21-40006081;