chr11-128485020-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001143820.2(ETS1):​c.665C>T​(p.Pro222Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ETS1
NM_001143820.2 missense

Scores

3
7
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.96
Variant links:
Genes affected
ETS1 (HGNC:3488): (ETS proto-oncogene 1, transcription factor) This gene encodes a member of the ETS family of transcription factors, which are defined by the presence of a conserved ETS DNA-binding domain that recognizes the core consensus DNA sequence GGAA/T in target genes. These proteins function either as transcriptional activators or repressors of numerous genes, and are involved in stem cell development, cell senescence and death, and tumorigenesis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[provided by RefSeq, Jul 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ETS1NM_001143820.2 linkuse as main transcriptc.665C>T p.Pro222Leu missense_variant 7/10 ENST00000392668.8 NP_001137292.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ETS1ENST00000392668.8 linkuse as main transcriptc.665C>T p.Pro222Leu missense_variant 7/101 NM_001143820.2 ENSP00000376436 P14921-3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152004
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251036
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135644
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461746
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
727188
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152004
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74262
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000302

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 submitterclinical testingAmbry GeneticsMay 17, 2023The c.665C>T (p.P222L) alteration is located in exon 7 (coding exon 6) of the ETS1 gene. This alteration results from a C to T substitution at nucleotide position 665, causing the proline (P) at amino acid position 222 to be replaced by a leucine (L). 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
0.48
BayesDel_addAF
Uncertain
0.091
D
BayesDel_noAF
Benign
-0.11
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
.;.;.;D
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Benign
0.032
D
MetaRNN
Uncertain
0.52
D;D;D;D
MetaSVM
Benign
-0.80
T
MutationAssessor
Benign
1.6
.;L;L;L
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-2.1
N;N;N;N
REVEL
Benign
0.27
Sift
Benign
0.031
D;D;D;D
Sift4G
Benign
0.20
T;T;D;T
Polyphen
0.42
.;.;.;B
Vest4
0.74
MutPred
0.36
.;Loss of disorder (P = 0.0253);Loss of disorder (P = 0.0253);Loss of disorder (P = 0.0253);
MVP
0.50
MPC
0.93
ClinPred
0.67
D
GERP RS
5.8
Varity_R
0.16
gMVP
0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1246153557; hg19: chr11-128354915; API