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
Consequence
NM_001987.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ETV6 | NM_001987.5 | c.1106G>A | p.Arg369Gln | missense_variant | Exon 6 of 8 | ENST00000396373.9 | NP_001978.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727242
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
Thrombocytopenia 5 Pathogenic:2
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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
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) -
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
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
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
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Neoplasm Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at