rs387906629
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_032638.5(GATA2):c.1192C>T(p.Arg398Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R398Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_032638.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GATA2 | NM_001145661.2 | c.1192C>T | p.Arg398Trp | missense_variant | 7/7 | ENST00000487848.6 | |
GATA2 | NM_032638.5 | c.1192C>T | p.Arg398Trp | missense_variant | 6/6 | ENST00000341105.7 | |
GATA2 | NM_001145662.1 | c.1150C>T | p.Arg384Trp | missense_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GATA2 | ENST00000341105.7 | c.1192C>T | p.Arg398Trp | missense_variant | 6/6 | 1 | NM_032638.5 | P1 | |
GATA2 | ENST00000487848.6 | c.1192C>T | p.Arg398Trp | missense_variant | 7/7 | 1 | NM_001145661.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727228
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Monocytopenia with susceptibility to infections Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 08, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 17, 2022 | PS4, PM1, PM2, PM5, PP2, PP3, PP5 - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 09, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 13, 2022 | PP3, PM1, PM2_supporting, PS3, PS4 - |
Leukemia, acute myeloid, susceptibility to Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 14, 2016 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 15, 2023 | The p.R398W pathogenic mutation (also known as c.1192C>T), located in coding exon 5 of the GATA2 gene, results from a C to T substitution at nucleotide position 1192. The arginine at codon 398 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been detected in multiple unrelated individuals with GATA2 deficiency syndrome (Dickinson RE et al. Blood, 2011 Sep;118:2656-8; Hsu AP et al. Blood, 2011 Sep;118:2653-5; Churpek JE et al. Blood, 2015 Nov;126:2484-90; Mardahl M et al. Br J Haematol, 2019 Aug;186:471-476; West RR et al. Blood Adv, 2022 Feb;6:793-807). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 07, 2023 | ClinVar contains an entry for this variant (Variation ID: 29709). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 398 of the GATA2 protein (p.Arg398Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with GATA2 deficiency (PMID: 21670465, 21765025). 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 GATA2 protein function. Experimental studies have shown that this missense change affects GATA2 function (PMID: 29882021). For these reasons, this variant has been classified as Pathogenic. - |
Deafness-lymphedema-leukemia syndrome;CN300066:GATA2 deficiency with susceptibility to MDS/AML Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | Molecular Pathology Research Laboratory, SA Pathology | Jul 06, 2021 | PS3, PS4, PM1, PM2, PM5, PP1_Moderate, PP3 - |
Acute myeloid leukemia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at