rs463269

Positions:

• chr21-38642513-C-T
• chr21-38642513-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000398919.6(ERG):​c.-150+18009G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.808 in 152,078 control chromosomes in the GnomAD database, including 49,975 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 0.81 (49975 hom., cov: 32)
• Consequence: ERG ENST00000398919.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.334

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERG	NM_001136154.1	c.-150+19145G>A		intron_variant			NP_001129626.1
ERG	NM_001243428.1	c.-150+18009G>A		intron_variant			NP_001230357.1
ERG	NM_001243432.2	c.-150+19145G>A		intron_variant			NP_001230361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000398919.6	c.-150+18009G>A		intron_variant		1		ENSP00000381891	A1
ERG	ENST00000468474.5	n.37+19145G>A		intron_variant, non_coding_transcript_variant		1
ERG	ENST00000485493.1	n.37+19145G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.808 AC: 122754 AN: 151960 Hom.: 49913 Cov.: 32

Gnomad AFR AF: 0.910

Gnomad AMI AF: 0.859

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.826

Gnomad EAS AF: 0.741

Gnomad SAS AF: 0.807

Gnomad FIN AF: 0.725

Gnomad MID AF: 0.793

Gnomad NFE AF: 0.770

Gnomad OTH AF: 0.780

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

GnomAD4 genome AF: 0.808 AC: 122875 AN: 152078 Hom.: 49975 Cov.: 32 AF XY: 0.806 AC XY: 59891 AN XY: 74318

Gnomad4 AFR AF: 0.910

Gnomad4 AMR AF: 0.776

Gnomad4 ASJ AF: 0.826

Gnomad4 EAS AF: 0.741

Gnomad4 SAS AF: 0.808

Gnomad4 FIN AF: 0.725

Gnomad4 NFE AF: 0.770

Gnomad4 OTH AF: 0.781

Alfa AF: 0.791 Hom.: 7490

Bravo AF: 0.816

Asia WGS AF: 0.771 AC: 2683 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.74
DANN	Benign	0.40

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs463269; hg19: chr21-40014437; COSMIC: COSV67395050;