Genetic Variant ERG:p.Gly226Asp (chr21-38400642-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_182918.4(ERG):c.677G>A(p.Gly226Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000552 in 1,449,028 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G226V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ERG
NM_182918.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.63

Publications

0 publications found

Variant links:

COSMIC-nc: COSV55731356

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERG	NM_182918.4 link	c.677G>A	p.Gly226Asp	missense_variant	Exon 6 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.677G>A	p.Gly226Asp	missense_variant	Exon 6 of 10	1	NM_182918.4	ENSP00000288319.7		P11308-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000552

AC:

AN:

1449028

Hom.:

Cov.:

AF XY:

0.00000557

AC XY:

AN XY:

718220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33116

American (AMR)

AF:

0.00

AC:

AN:

44372

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25946

East Asian (EAS)

AF:

0.00

AC:

AN:

39366

South Asian (SAS)

AF:

0.00

AC:

AN:

85902

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5510

European-Non Finnish (NFE)

AF:

0.00000635

AC:

AN:

1101806

Other (OTH)

AF:

0.0000167

AC:

AN:

59718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

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

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.49

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

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

PhyloP100

5.6

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.63

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

REVEL

Benign

0.28

Sift

Benign

0.29

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

Sift4G

Benign

0.28

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

Polyphen

0.89, 0.70

.;P;P;.;.;P;.

Vest4

0.64

MutPred

0.42

.;.;Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;Gain of loop (P = 0.1069);.;

MVP

0.36

MPC

1.2

ClinPred

0.72

GERP RS

5.1

Varity_R

0.21

gMVP

0.79

Mutation Taster

=47/53

disease causing

(source)

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

Publications

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21-38400642-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over