21-38422958-T-G

Variant names:

• chr21-38422958-T-G
• rs1571704
• NM_182918.4:c.388+452A>C

Variant summary

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

The NM_182918.4(ERG):​c.388+452A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.955 in 152,184 control chromosomes in the GnomAD database, including 69,388 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 0.95 (69388 hom., cov: 31)
• Consequence: ERG NM_182918.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.335
• Publications: 2 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.98 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.388+452A>C		intron	N/A	NP_891548.1
	ERG	NM_001136154.1		c.409+452A>C		intron	N/A	NP_001129626.1
	ERG	NM_001243428.1		c.409+452A>C		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.388+452A>C		intron	N/A	ENSP00000288319.7
	ERG	ENST00000398919.6	TSL:1	c.409+452A>C		intron	N/A	ENSP00000381891.2
	ERG	ENST00000398905.5	TSL:1	c.388+452A>C		intron	N/A	ENSP00000381877.1

Frequencies

GnomAD3 genomes AF: 0.954 AC: 145137 AN: 152066 Hom.: 69322 Cov.: 31

Gnomad AFR AF: 0.988

Gnomad AMI AF: 0.984

Gnomad AMR AF: 0.937

Gnomad ASJ AF: 0.929

Gnomad EAS AF: 0.988

Gnomad SAS AF: 0.961

Gnomad FIN AF: 0.956

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.936

Gnomad OTH AF: 0.940

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

GnomAD4 genome AF: 0.955 AC: 145262 AN: 152184 Hom.: 69388 Cov.: 31 AF XY: 0.955 AC XY: 71079 AN XY: 74390

African (AFR) AF: 0.988 AC: 41051 AN: 41532

American (AMR) AF: 0.937 AC: 14324 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 3226 AN: 3472

East Asian (EAS) AF: 0.988 AC: 5087 AN: 5148

South Asian (SAS) AF: 0.962 AC: 4631 AN: 4816

European-Finnish (FIN) AF: 0.956 AC: 10132 AN: 10602

Middle Eastern (MID) AF: 0.929 AC: 273 AN: 294

European-Non Finnish (NFE) AF: 0.936 AC: 63653 AN: 68008

Other (OTH) AF: 0.941 AC: 1988 AN: 2112

Alfa AF: 0.942 Hom.: 122577

Bravo AF: 0.954

Asia WGS AF: 0.971 AC: 3379 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.5
DANN	Benign	0.43
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: rs1571704; hg19: chr21-39794880;