rs746362966
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_032638.5(GATA2):āc.413T>Cā(p.Leu138Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000716 in 1,563,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. L138L) has been classified as Likely benign.
Frequency
Consequence
NM_032638.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GATA2 | NM_001145661.2 | c.413T>C | p.Leu138Pro | missense_variant | 4/7 | ENST00000487848.6 | |
GATA2 | NM_032638.5 | c.413T>C | p.Leu138Pro | missense_variant | 3/6 | ENST00000341105.7 | |
GATA2 | NM_001145662.1 | c.413T>C | p.Leu138Pro | missense_variant | 3/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GATA2 | ENST00000341105.7 | c.413T>C | p.Leu138Pro | missense_variant | 3/6 | 1 | NM_032638.5 | P1 | |
GATA2 | ENST00000487848.6 | c.413T>C | p.Leu138Pro | missense_variant | 4/7 | 1 | NM_001145661.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152010Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000422 AC: 7AN: 165748Hom.: 0 AF XY: 0.0000450 AC XY: 4AN XY: 88882
GnomAD4 exome AF: 0.0000758 AC: 107AN: 1411808Hom.: 0 Cov.: 36 AF XY: 0.0000660 AC XY: 46AN XY: 697498
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152010Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74228
ClinVar
Submissions by phenotype
Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 138 of the GATA2 protein (p.Leu138Pro). This variant is present in population databases (rs746362966, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GATA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 404085). 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) has been performed at Invitae 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. - |
Deafness-lymphedema-leukemia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Predisposition to myelodysplastic syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 08, 2023 | The GATA2 c.413T>C (p.Leu138Pro) missense change has a maximum subpopulation frequency of 0.009% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals presenting with GATA2-associated clinical phenotypes. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Acute myeloid leukemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 22, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at