rs724159946

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001987.5(ETV6):​c.1106G>A​(p.Arg369Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ETV6
NM_001987.5 missense

Scores

9
7
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
ETV6 (HGNC:3495): (ETS variant transcription factor 6) This gene encodes an ETS family transcription factor. The product of this gene contains two functional domains: a N-terminal pointed (PNT) domain that is involved in protein-protein interactions with itself and other proteins, and a C-terminal DNA-binding domain. Gene knockout studies in mice suggest that it is required for hematopoiesis and maintenance of the developing vascular network. This gene is known to be involved in a large number of chromosomal rearrangements associated with leukemia and congenital fibrosarcoma. [provided by RefSeq, Sep 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.921
PP5
Variant 12-11884541-G-A is Pathogenic according to our data. Variant chr12-11884541-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ETV6NM_001987.5 linkc.1106G>A p.Arg369Gln missense_variant Exon 6 of 8 ENST00000396373.9 NP_001978.1 P41212A0A0S2Z3C9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ETV6ENST00000396373.9 linkc.1106G>A p.Arg369Gln missense_variant Exon 6 of 8 1 NM_001987.5 ENSP00000379658.3 P41212

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152160
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461882
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727242
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152160
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Thrombocytopenia 5 Pathogenic:2
Feb 01, 2015
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Mar 21, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: ETV6 c.1106G>A (p.Arg369Gln) results in a conservative amino acid change located in the ETS domain (IPR000418) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251442 control chromosomes. c.1106G>A has been reported in the literature in multiple heterozygous individuals affected with Thrombocytopenia, showing evidence of familial segregation with disease (e.g. Zhang_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing the variant is associated with abrogated DNA binding, altered subcellular localization, decreased transcriptional repression in a dominant-negative fashion and impaired hematopoiesis (e.g. Zhang_2015). The following publication has been ascertained in the context of this evaluation (PMID: 25581430). ClinVar contains an entry for this variant (Variation ID: 162221). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2
Apr 04, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: negative effect on binding, altered subcellular localization, decreased transcriptional repression in a dominant-negative fashion, and impaired hematopoiesis (Zhang et al., 2015; Topka et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27663637, 26102509, 25581430, 26522332, 28555414, 29034503, 27365488, 28637624, 32841218) -

Sep 03, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg369 amino acid residue in ETV6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26522332, 27365488, 31064749). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ETV6 function (PMID: 25581430). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ETV6 protein function. ClinVar contains an entry for this variant (Variation ID: 162221). This missense change has been observed in individual(s) with ETV6-related thrombocytopenia (PMID: 25581430). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 369 of the ETV6 protein (p.Arg369Gln). -

ETV6-related disorder Pathogenic:1
Dec 05, 2022
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The ETV6 c.1106G>A variant is predicted to result in the amino acid substitution p.Arg369Gln. This variant has been reported in individuals with Thrombocytopenia and/or hematologic malignancy (Zhang et al. 2015. PubMed ID: 25581430; Moriyama et al. 2015. PubMed ID: 26522332; Drazer et al. 2022. PubMed ID: 35537115). Functional study showed this variant abrogated DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative fashion and impair hematopoiesis (Zhang et al. 2015. PubMed ID: 25581430). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted likely pathogenic. -

Inborn genetic diseases Pathogenic:1
Dec 20, 2023
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R369Q variant (also known as c.1106G>A), located in coding exon 6 of the ETV6 gene, results from a G to A substitution at nucleotide position 1106. The arginine at codon 369 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. This alteration has been reported in multiple individuals with a personal and/or family history that is consistent with ETV6-related disease (Drazer MW et al. Blood Adv 2022 Aug;6(15):4357-4359; Moriyama T et al. Lancet Oncol 2015 Dec;16(16):1659-66; Leinøe E et al. Br J Haematol 2019 Jul;186(2):373-376). Multiple functional studies have demonstrated that this alteration impacts the ability of ETV6 to bind DNA and repress target gene function (Fisher MH et al. JCI Insight 2020 Sep;5(18); Topka S et al. PLoS Genet 2015 Jun;11(6):e1005262; Nishii R et al. Blood 2021 Jan;137(3):364-373). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Thrombocytopenia;C0376545:Hematologic neoplasm Pathogenic:1
Nov 30, 2014
Akiko Shimamura Lab, Fred Hutchinson Cancer Research Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Neoplasm Other:1
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: -
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.070
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.85
D
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.92
D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
L
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-3.2
D
REVEL
Pathogenic
0.72
Sift
Uncertain
0.0050
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.96
MutPred
0.66
Loss of MoRF binding (P = 0.0294);
MVP
0.69
MPC
3.0
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.68
gMVP
0.84

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: rs724159946; hg19: chr12-12037475; COSMIC: COSV56765799; COSMIC: COSV56765799; API