rs9976318

Variant names:

• chr21-38618766-A-G
• rs9976318
• ENST00000398919.6:c.-149-33821T>C

Variant summary

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

The NM_001136154.1(ERG):​c.-149-33821T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0564 in 150,842 control chromosomes in the GnomAD database, including 314 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 0.056 (314 hom., cov: 32)
• Consequence: ERG NM_001136154.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• Publications: 3 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0776 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136154.1. 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_001136154.1		c.-149-33821T>C		intron	N/A	NP_001129626.1	P11308-3
	ERG	NM_001243428.1		c.-149-33821T>C		intron	N/A	NP_001230357.1	P11308-3
	ERG	NM_004449.4		c.-149-33821T>C		intron	N/A	NP_004440.1	P11308-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	ENST00000398919.6	TSL:1	c.-149-33821T>C		intron	N/A	ENSP00000381891.2	P11308-3
	ERG	ENST00000468474.5	TSL:1	n.38-33821T>C		intron	N/A
	ERG	ENST00000485493.1	TSL:1	n.38-33821T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0564 AC: 8496 AN: 150724 Hom.: 314 Cov.: 32

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0579

Gnomad ASJ AF: 0.0900

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0601

Gnomad FIN AF: 0.0855

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0794

Gnomad OTH AF: 0.0514

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

GnomAD4 genome AF: 0.0564 AC: 8503 AN: 150842 Hom.: 314 Cov.: 32 AF XY: 0.0557 AC XY: 4110 AN XY: 73748

African (AFR) AF: 0.0136 AC: 546 AN: 40212

American (AMR) AF: 0.0584 AC: 891 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0900 AC: 312 AN: 3466

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5168

South Asian (SAS) AF: 0.0602 AC: 290 AN: 4820

European-Finnish (FIN) AF: 0.0855 AC: 906 AN: 10602

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0794 AC: 5399 AN: 68004

Other (OTH) AF: 0.0509 AC: 107 AN: 2104

Alfa AF: 0.0709 Hom.: 323

Bravo AF: 0.0525

Asia WGS AF: 0.0290 AC: 99 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.32
DANN	Benign	0.57
PhyloP100		-0.018
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: rs9976318; hg19: chr21-39990690;