21-38392430-G-A

Variant names:

• chr21-38392430-G-A
• rs1395772766
• NM_182918.4:c.760C>T

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.760C>T​(p.Pro254Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ERG NM_182918.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.01
• Publications: 1 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=0.1392177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_182918.4	c.760C>T	p.Pro254Ser	missense_variant	Exon 7 of 10	ENST00000288319.12	NP_891548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000288319.12	c.760C>T	p.Pro254Ser	missense_variant	Exon 7 of 10	1	NM_182918.4	ENSP00000288319.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394506 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 687856

African (AFR) AF: 0.00 AC: 0 AN: 31374

American (AMR) AF: 0.00 AC: 0 AN: 34432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24626

East Asian (EAS) AF: 0.00 AC: 0 AN: 36286

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 77202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077440

Other (OTH) AF: 0.00 AC: 0 AN: 57638

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.781C>T (p.P261S) alteration is located in exon 9 (coding exon 7) of the ERG gene. This alteration results from a C to T substitution at nucleotide position 781, causing the proline (P) at amino acid position 261 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.58
DEOGEN2	Benign	0.31	.;.;.;.;T;.;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D;D;D;.;.;D;D;D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	.;.;.;.;N;.;.;N
PhyloP100		3.0
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.26	N;N;N;N;N;N;N;N
REVEL	Benign	0.098
Sift	Benign	0.79	T;T;T;T;T;T;T;T
Sift4G	Benign	0.79	T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;B;B;.;B
Vest4		0.51
MutPred		0.31		.;.;.;.;Loss of catalytic residue at P261 (P = 0.0014);.;.;Loss of catalytic residue at P261 (P = 0.0014);
MVP		0.42
MPC		0.97
ClinPred		0.59	D
GERP RS		4.9
Varity_R		0.096
gMVP		0.48
Mutation Taster		=73/27	polymorphism

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: rs1395772766; hg19: chr21-39764352;