3-128481938-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2
The NM_032638.5(GATA2):c.1024G>A(p.Ala342Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,613,364 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A342S) has been classified as Uncertain significance.
Frequency
Consequence
NM_032638.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GATA2 | NM_032638.5 | c.1024G>A | p.Ala342Thr | missense_variant | Exon 5 of 6 | ENST00000341105.7 | NP_116027.2 | |
GATA2 | NM_001145661.2 | c.1024G>A | p.Ala342Thr | missense_variant | Exon 6 of 7 | NP_001139133.1 | ||
GATA2 | NM_001145662.1 | c.1018-36G>A | intron_variant | Intron 4 of 5 | NP_001139134.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152174Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249436Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135254
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461190Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 726902
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74334
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The p.A342T variant (also known as c.1024G>A), located in coding exon 4 of the GATA2 gene, results from a G to A substitution at nucleotide position 1024. The alanine at codon 342 is replaced by threonine, an amino acid with similar properties. This alteration was detected in the germline of a pediatric patient with AML (Shiba N et al. Br J Haematol, 2014 Jan;164:142-5). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 342 of the GATA2 protein (p.Ala342Thr). This variant is present in population databases (rs751285156, gnomAD 0.006%). This missense change has been observed in individual(s) with acute myeloid leukemia (PMID: 24033149). ClinVar contains an entry for this variant (Variation ID: 652480). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GATA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Acute myeloid leukemia;C3279664:Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections;C3463824:Myelodysplastic syndrome Uncertain:1
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Deafness-lymphedema-leukemia syndrome Uncertain:1
A GATA2 c.1024G>A (p.Ala342Thr) variant was identified at a near heterozygous allelic fraction of 48.8%, a frequency which may be consistent with it being of germline origin. This variant has been reported in a germline state in a patient with de novo pediatric acute myeloid leukemia (Shiba N et al., PMID: 24033149). This variant is observed on 35/1,613,364 alleles in the general population (gnomAD v4.1.0). Computational predictors are uncertain as to the impact of this variant on GATA2 function. Due to limited information and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -
not provided Uncertain:1
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; Observed as a germline variant in an individual with pediatric acute myeloid leukemia (AML) (PMID: 24033149); This variant is associated with the following publications: (PMID: 25707267, 24033149) -
Deafness-lymphedema-leukemia syndrome;CN300066:GATA2 deficiency with susceptibility to MDS/AML Uncertain:1
No criteria satisfied -
Acute myeloid leukemia Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at