21-38480628-A-T

Variant names:

• chr21-38480628-A-T
• rs7275212
• NM_182918.4:c.18+17735T>A

Variant summary

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

The NM_182918.4(ERG):​c.18+17735T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.031 (47 hom., cov: 19)
• Consequence: ERG NM_182918.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.343
• Publications: 13 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.104 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.18+17735T>A		intron	N/A	NP_891548.1
	ERG	NM_001136154.1		c.40-35007T>A		intron	N/A	NP_001129626.1
	ERG	NM_001243428.1		c.40-35007T>A		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.18+17735T>A		intron	N/A	ENSP00000288319.7
	ERG	ENST00000398919.6	TSL:1	c.40-35007T>A		intron	N/A	ENSP00000381891.2
	ERG	ENST00000398905.5	TSL:1	c.18+17735T>A		intron	N/A	ENSP00000381877.1

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 2515 AN: 81620 Hom.: 47 Cov.: 19

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0284

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.0488

Gnomad FIN AF: 0.0658

Gnomad MID AF: 0.0897

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0375

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

GnomAD4 genome AF: 0.0308 AC: 2512 AN: 81662 Hom.: 47 Cov.: 19 AF XY: 0.0330 AC XY: 1235 AN XY: 37452

African (AFR) AF: 0.0378 AC: 844 AN: 22344

American (AMR) AF: 0.0284 AC: 153 AN: 5380

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 37 AN: 2294

East Asian (EAS) AF: 0.114 AC: 336 AN: 2954

South Asian (SAS) AF: 0.0485 AC: 117 AN: 2412

European-Finnish (FIN) AF: 0.0658 AC: 148 AN: 2248

Middle Eastern (MID) AF: 0.0972 AC: 7 AN: 72

European-Non Finnish (NFE) AF: 0.0196 AC: 829 AN: 42350

Other (OTH) AF: 0.0372 AC: 41 AN: 1102

Alfa AF: 0.0163 Hom.: 28

Asia WGS AF: 0.0490 AC: 171 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.33
DANN	Benign	0.38
PhyloP100		-0.34
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: rs7275212; hg19: chr21-39852551;