chr21-38402573-C-T

Position:

• chr21-38402573-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.28

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
ERG	NM_182918.4	c.657G>A	p.Met219Ile	missense_variant	5/10	ENST00000288319.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERG	ENST00000288319.12	c.657G>A	p.Met219Ile	missense_variant	5/10	1	NM_182918.4	P4

Frequencies

GnomAD3 genomes AF: 0.000998 AC: 150 AN: 150234 Hom.: 1 Cov.: 30

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

GnomAD3 exomes AF: 0.000308 AC: 77 AN: 250204 Hom.: 0 AF XY: 0.000163 AC XY: 22 AN XY: 135352

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 SAS 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.: 0 Cov.: 31 AF XY: 0.000126 AC XY: 91 AN XY: 719828

Gnomad4 AFR exome AF: 0.00363

Gnomad4 AMR exome AF: 0.000546

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000435

Gnomad4 OTH exome AF: 0.000421

GnomAD4 genome AF: 0.00100 AC: 151 AN: 150360 Hom.: 1 Cov.: 30 AF XY: 0.000844 AC XY: 62 AN XY: 73430

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.000199

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000237 Hom.: 0

Bravo AF: 0.00124

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000420 AC: 51

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acute lymphoid leukemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostics Laboratory, National Institute of Medical Genomics

Sep 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
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	D
LIST_S2	Uncertain	0.97	D;D;D;D;.;.;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;.;.;.;L;L;.;L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
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	T
GERP RS		5.6
Varity_R		0.21
gMVP		0.78

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

LitVar

Other links and lift over

dbSNP: rs149928865; hg19: chr21-39774495; COSMIC: COSV55733939; COSMIC: COSV55733939;