3-128481270-G-A
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_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 (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
GATA2
NM_032638.5 missense
NM_032638.5 missense
Scores
17
1
1
Clinical Significance
Conservation
PhyloP100: 4.11
Genes affected
GATA2 (HGNC:4171): (GATA binding protein 2) This gene encodes a member of the GATA family of zinc-finger transcription factors that are named for the consensus nucleotide sequence they bind in the promoter regions of target genes. The encoded protein plays an essential role in regulating transcription of genes involved in the development and proliferation of hematopoietic and endocrine cell lineages. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Mar 2009]
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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, 0.925
PP5
Variant 3-128481270-G-A is Pathogenic according to our data. Variant chr3-128481270-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-128481270-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GATA2 | NM_032638.5 | c.1192C>T | p.Arg398Trp | missense_variant | Exon 6 of 6 | ENST00000341105.7 | NP_116027.2 | |
GATA2 | NM_001145661.2 | c.1192C>T | p.Arg398Trp | missense_variant | Exon 7 of 7 | NP_001139133.1 | ||
GATA2 | NM_001145662.1 | c.1150C>T | p.Arg384Trp | missense_variant | Exon 6 of 6 | NP_001139134.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
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 exome
AF:
AC:
1
AN:
1461838
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
727228
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 13, 2022 | PP3, PM1, PM2_supporting, PS3, PS4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 13, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 09, 2016 | - - |
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 - |
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 | Labcorp Genetics (formerly Invitae), Labcorp | Nov 05, 2024 | 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). ClinVar contains an entry for this variant (Variation ID: 29709). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GATA2 protein function with a positive predictive value of 95%. 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 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;M
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Gain of glycosylation at S401 (P = 0.0062);.;Gain of glycosylation at S401 (P = 0.0062);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at