chr21-38402557-CTG-C

Variant names:

• chr21-38402557-CTG-C
• NM_182918.4:c.671_672delCA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_182918.4(ERG):​c.671_672delCA​(p.Thr224ArgfsTer15) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ERG NM_182918.4 frameshift, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.93
• Publications: 0 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-38402557-CTG-C is Pathogenic according to our data. Variant chr21-38402557-CTG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2637894.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	NM_182918.4	MANE Select	c.671_672delCA	p.Thr224ArgfsTer15	frameshift splice_region	Exon 5 of 10	NP_891548.1	P11308-4
	ERG	NM_001136154.1		c.692_693delCA	p.Thr231ArgfsTer15	frameshift splice_region	Exon 7 of 12	NP_001129626.1	P11308-3
	ERG	NM_001243428.1		c.692_693delCA	p.Thr231ArgfsTer15	frameshift splice_region	Exon 7 of 12	NP_001230357.1	P11308-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERG	ENST00000288319.12	TSL:1 MANE Select	c.671_672delCA	p.Thr224ArgfsTer15	frameshift splice_region	Exon 5 of 10	ENSP00000288319.7	P11308-4
	ERG	ENST00000398919.6	TSL:1	c.692_693delCA	p.Thr231ArgfsTer15	frameshift splice_region	Exon 7 of 12	ENSP00000381891.2	P11308-3
	ERG	ENST00000398905.5	TSL:1	c.671_672delCA	p.Thr224ArgfsTer5	frameshift splice_region	Exon 5 of 9	ENSP00000381877.1	B5MDW0

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Lymphatic malformation 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr21-39774479;