chr21-38392382-A-C

Variant names:

• chr21-38392382-A-C
• rs557419877
• NM_182918.4:c.808T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182918.4(ERG):​c.808T>G​(p.Ser270Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S270T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERG NM_182918.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.08
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15853795).

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.808T>G	p.Ser270Ala	missense	Exon 7 of 10	NP_891548.1	P11308-4
	ERG	NM_001136154.1		c.829T>G	p.Ser277Ala	missense	Exon 9 of 12	NP_001129626.1	P11308-3
	ERG	NM_001243428.1		c.829T>G	p.Ser277Ala	missense	Exon 9 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.808T>G	p.Ser270Ala	missense	Exon 7 of 10	ENSP00000288319.7	P11308-4
	ERG	ENST00000398919.6	TSL:1	c.829T>G	p.Ser277Ala	missense	Exon 9 of 12	ENSP00000381891.2	P11308-3
	ERG	ENST00000398905.5	TSL:1	c.736T>G	p.Ser246Ala	missense	Exon 6 of 9	ENSP00000381877.1	B5MDW0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.072
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N
PhyloP100		3.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.016
Sift	Benign	0.20	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.38
MutPred		0.27		Loss of glycosylation at S277 (P = 0.0012)
MVP		0.64
MPC		0.82
ClinPred		0.34	T
GERP RS		3.5
Varity_R		0.080
gMVP		0.49
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs557419877; hg19: chr21-39764304;