rs146554939
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_032638.5(GATA2):c.1274C>T(p.Ser425Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,614,128 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_032638.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GATA2 | NM_032638.5 | c.1274C>T | p.Ser425Leu | missense_variant | Exon 6 of 6 | ENST00000341105.7 | NP_116027.2 | |
GATA2 | NM_001145661.2 | c.1274C>T | p.Ser425Leu | missense_variant | Exon 7 of 7 | NP_001139133.1 | ||
GATA2 | NM_001145662.1 | c.1232C>T | p.Ser411Leu | missense_variant | Exon 6 of 6 | NP_001139134.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000525 AC: 8AN: 152238Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251472Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135920
GnomAD4 exome AF: 0.0000493 AC: 72AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29AN XY: 727244
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152238Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74370
ClinVar
Submissions by phenotype
not specified Uncertain:1
DNA sequence analysis of the GATA2 gene demonstrated a sequence change, c.1274C>T, in exon 6 that results in an amino acid change, p.Ser425Leu. This sequence change has been described in gnomAD with a frequency of 0.0028% in the African sub-population (dbSNP rs146554939). The p.Ser425Leu change affects a moderately conserved amino acid residue located in a domain of the GATA2 protein that is known to be functional. The p.Ser425Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with GATA2-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Ser425Leu change remains unknown at this time. -
GATA2-related disorder Uncertain:1
The GATA2 c.1274C>T variant is predicted to result in the amino acid substitution p.Ser425Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-128200031-G-A) and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/472441/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections Uncertain:1
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 425 of the GATA2 protein (p.Ser425Leu). This variant is present in population databases (rs146554939, gnomAD 0.006%). 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: 472441). 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. -
not provided Uncertain:1
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Uncertain:1
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Acute myeloid leukemia Uncertain:1
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Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at