Genetic Variant ERG:c.19-7468G>A (chr21-38453089-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_182918.4(ERG):c.19-7468G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 152,132 control chromosomes in the GnomAD database, including 43,054 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.75 ( 43054 hom., cov: 33)

Consequence

ERG
NM_182918.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.99

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.866 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERG	NM_182918.4	MANE Select	c.19-7468G>A	intron	N/A	NP_891548.1	P11308-4
ERG	NM_001136154.1		c.40-7468G>A	intron	N/A	NP_001129626.1	P11308-3
ERG	NM_001243428.1		c.40-7468G>A	intron	N/A	NP_001230357.1	P11308-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERG	ENST00000288319.12	TSL:1 MANE Select	c.19-7468G>A	intron	N/A	ENSP00000288319.7	P11308-4
ERG	ENST00000398919.6	TSL:1	c.40-7468G>A	intron	N/A	ENSP00000381891.2	P11308-3
ERG	ENST00000398905.5	TSL:1	c.19-7468G>A	intron	N/A	ENSP00000381877.1	B5MDW0

Frequencies

GnomAD3 genomes

AF:

0.749

AC:

113888

AN:

152014

Hom.:

43027

Cov.:

show subpopulations

Gnomad AFR

AF:

0.643

Gnomad AMI

AF:

0.939

Gnomad AMR

AF:

0.782

Gnomad ASJ

AF:

0.844

Gnomad EAS

AF:

0.887

Gnomad SAS

AF:

0.762

Gnomad FIN

AF:

0.749

Gnomad MID

AF:

0.791

Gnomad NFE

AF:

0.787

Gnomad OTH

AF:

0.764

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

GnomAD4 genome

AF:

0.749

AC:

113956

AN:

152132

Hom.:

43054

Cov.:

AF XY:

0.749

AC XY:

55684

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.642

AC:

26650

AN:

41482

American (AMR)

AF:

0.783

AC:

11975

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.844

AC:

2923

AN:

3462

East Asian (EAS)

AF:

0.887

AC:

4587

AN:

5170

South Asian (SAS)

AF:

0.761

AC:

3660

AN:

4810

European-Finnish (FIN)

AF:

0.749

AC:

7925

AN:

10578

Middle Eastern (MID)

AF:

0.793

AC:

233

AN:

294

European-Non Finnish (NFE)

AF:

0.787

AC:

53529

AN:

68016

Other (OTH)

AF:

0.766

AC:

1618

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1473

2946

4420

5893

7366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

852

1704

2556

3408

4260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.781

Hom.:

79514

Bravo

AF:

0.753

Asia WGS

AF:

0.805

AC:

2801

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.073

(source)

DANN

Benign

0.61

PhyloP100

-3.0

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over