chr21-38575684-G-A
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The ENST00000398919.6(ERG):c.17C>T(p.Pro6Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000161 in 1,613,682 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00017 ( 0 hom. )
Consequence
ERG
ENST00000398919.6 missense
ENST00000398919.6 missense
Scores
2
6
7
Clinical Significance
Conservation
PhyloP100: 5.82
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAd4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERG | NM_001136154.1 | c.17C>T | p.Pro6Leu | missense_variant | 3/12 | ||
ERG | NM_001243428.1 | c.17C>T | p.Pro6Leu | missense_variant | 3/12 | ||
ERG | NM_004449.4 | c.17C>T | p.Pro6Leu | missense_variant | 3/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERG | ENST00000398919.6 | c.17C>T | p.Pro6Leu | missense_variant | 3/12 | 1 | A1 | ||
ERG | ENST00000468474.5 | n.203C>T | non_coding_transcript_exon_variant | 3/8 | 1 | ||||
ERG | ENST00000485493.1 | n.203C>T | non_coding_transcript_exon_variant | 3/5 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152150Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251270Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135808
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GnomAD4 exome AF: 0.000172 AC: 251AN: 1461532Hom.: 0 Cov.: 30 AF XY: 0.000183 AC XY: 133AN XY: 727072
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 152150Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74308
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 12, 2021 | The c.17C>T (p.P6L) alteration is located in exon 3 (coding exon 1) of the ERG gene. This alteration results from a C to T substitution at nucleotide position 17, causing the proline (P) at amino acid position 6 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;L;L
MutationTaster
Benign
D;D;D;D;D;D
PROVEAN
Benign
N;N;N;N;N
REVEL
Benign
Sift
Pathogenic
D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
B;B;.;B;B
Vest4
MVP
MPC
0.62
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at