rs724159946

chr12-11884541-G-Achr12-11884541-G-Cchr12-11884541-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R369W) has been classified 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

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

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]

ETV6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a DNA_binding_region ETS (size 81) in uniprot entity ETV6_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_001987.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-11884540-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 626971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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/exons	MANE	UniProt
ETV6	NM_001987.5 linkuse as main transcript	c.1106G>A	p.Arg369Gln	missense_variant	6/8	ENST00000396373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETV6	ENST00000396373.9 linkuse as main transcript	c.1106G>A	p.Arg369Gln	missense_variant	6/8	1	NM_001987.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

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:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

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:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 03, 2023	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. 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 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). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2023	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) -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

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

Pathogenic, no assertion criteria provided

research

Akiko Shimamura Lab, Fred Hutchinson Cancer Research Center

Nov 30, 2014

- -

Thrombocytopenia 5

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2015

- -

ETV6-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.92

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.2

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.66

Loss of MoRF binding (P = 0.0294);

MVP

0.69

MPC

3.0

ClinPred

1.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over