chr21-38423439-G-T

Position:

• chr21-38423439-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_182918.4(ERG):​c.359C>A​(p.Thr120Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERG NM_182918.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.76

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERG	NM_182918.4	c.359C>A	p.Thr120Lys	missense_variant	3/10	ENST00000288319.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERG	ENST00000288319.12	c.359C>A	p.Thr120Lys	missense_variant	3/10	1	NM_182918.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2023

The c.380C>A (p.T127K) alteration is located in exon 5 (coding exon 3) of the ERG gene. This alteration results from a C to A substitution at nucleotide position 380, causing the threonine (T) at amino acid position 127 to be replaced by a lysine (K). 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	Uncertain	0.43
BayesDel_addAF	Benign	0.0070	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;T;.;.;.;T;T;.;.;T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.;.;D;D;D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;.;.;.;L;L;.;L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D;D;N;D;.
REVEL	Benign	0.21
Sift	Benign	0.071	T;D;T;D;D;T;D;D;D;T;.
Sift4G	Benign	0.32	T;T;T;T;T;T;T;T;T;T;D
Polyphen		0.84	P;.;B;.;P;P;.;P;.;P;.
Vest4		0.69
MutPred		0.33		.;.;.;.;Gain of ubiquitination at T127 (P = 0.0069);Gain of ubiquitination at T127 (P = 0.0069);Gain of ubiquitination at T127 (P = 0.0069);Gain of ubiquitination at T127 (P = 0.0069);.;Gain of ubiquitination at T127 (P = 0.0069);.;
MVP		0.45
MPC		0.48
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.43
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-39795361;