21-38402573-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_182918.4(ERG):c.657G>A(p.Met219Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000233 in 1,597,340 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 30)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

ERG
NM_182918.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.28

Publications

6 publications found

Variant links:

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

ERG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012736738).

BS2

High AC in GnomAd4 at 151 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_182918.4 link	c.657G>A	p.Met219Ile	missense_variant	Exon 5 of 10	ENST00000288319.12	NP_891548.1	P11308-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERG	ENST00000288319.12 link	c.657G>A	p.Met219Ile	missense_variant	Exon 5 of 10	1	NM_182918.4	ENSP00000288319.7		P11308-4

Frequencies

GnomAD3 genomes

AF:

0.000998

AC:

150

AN:

150234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000200

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000177

Gnomad OTH

AF:

0.000483

GnomAD2 exomes

AF:

0.000308

AC:

AN:

250204

AF XY:

0.000163

show subpopulations

Gnomad AFR exome

AF:

0.00284

Gnomad AMR exome

AF:

0.000641

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000794

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000153

AC:

221

AN:

1446980

Hom.:

Cov.:

AF XY:

0.000126

AC XY:

AN XY:

719828

show subpopulations

African (AFR)

AF:

0.00363

AC:

120

AN:

33042

American (AMR)

AF:

0.000546

AC:

AN:

43988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25528

East Asian (EAS)

AF:

0.00

AC:

AN:

38822

South Asian (SAS)

AF:

0.0000349

AC:

AN:

85888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51284

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.0000435

AC:

AN:

1103374

Other (OTH)

AF:

0.000421

AC:

AN:

59364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00100

AC:

151

AN:

150360

Hom.:

Cov.:

AF XY:

0.000844

AC XY:

AN XY:

73430

show subpopulations

African (AFR)

AF:

0.00327

AC:

134

AN:

40946

American (AMR)

AF:

0.000199

AC:

AN:

15058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

4948

South Asian (SAS)

AF:

0.00

AC:

AN:

4574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10342

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000177

AC:

AN:

67730

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000428

Hom.:

Bravo

AF:

0.00124

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000420

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Acute lymphoid leukemia

Uncertain:1

Sep 23, 2023

Genomic Diagnostics Laboratory, National Institute of Medical Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

.;T;.;.;.;T;T;.;.;T;T

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

D;D;D;D;.;.;D;D;D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.013

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

.;.;.;.;L;L;.;L;.;L;.

PhyloP100

6.3

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.1

N;N;N;N;N;N;N;N;N;N;.

REVEL

Benign

0.22

Sift

Benign

0.41

T;T;T;T;T;T;T;T;T;T;.

Sift4G

Benign

0.40

T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.15

B;.;P;.;B;B;.;B;.;B;.

Vest4

0.49

MutPred

0.42

.;.;.;.;Loss of phosphorylation at T231 (P = 0.0778);Loss of phosphorylation at T231 (P = 0.0778);Loss of phosphorylation at T231 (P = 0.0778);Loss of phosphorylation at T231 (P = 0.0778);.;Loss of phosphorylation at T231 (P = 0.0778);.;

MVP

0.75

MPC

1.1

ClinPred

0.021

GERP RS

5.6

Varity_R

0.21

gMVP

0.78

Mutation Taster

=33/67

disease causing

(source)

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

Publications

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21-38402573-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over