rs1466334264
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_001308093.3(GATA4):โc.241G>Aโ(p.Gly81Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000637 in 1,413,288 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 (โ โ ). Synonymous variant affecting the same amino acid position (i.e. G81G) has been classified as Likely benign.
Frequency
Consequence
NM_001308093.3 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 |
---|---|---|---|---|---|---|---|
GATA4 | NM_001308093.3 | c.241G>A | p.Gly81Arg | missense_variant | 2/7 | ENST00000532059.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GATA4 | ENST00000532059.6 | c.241G>A | p.Gly81Arg | missense_variant | 2/7 | 1 | NM_001308093.3 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152034Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000634 AC: 8AN: 1261254Hom.: 0 Cov.: 31 AF XY: 0.00000324 AC XY: 2AN XY: 617662
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152034Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74264
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 26, 2022 | - - |
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Sep 07, 2017 | p.Gly81Arg (c.241G>A) in exon 2 the GATA4 gene (NM_002052.3; chr8-11566062-G-A) SCICD Classification: Variant of uncertain significance based on preliminary data associating this gene with DCM and lack of case data and segregation data for this particular variant. Gene-level evidence: GATA4 is a transcription factor that controls gene expression and differentiation. There is sufficient evidence (per ClinGen working group) to associated GATA4 with multiple congenital heart defects. There is preliminary evidence to associate GATA4 with idiopathic DCM (Chen et al., 2012, Li et al., 2013). Case data (not including our patient): 0 รยท ClinVar: not present รยท Cases in the literature: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0")." Conservation data: The glycine at codon 81 is poorly conserved across species. Neighboring amino acids are also poorly conserved. Nearby pathogenic variants at this codon or neighboring codons: none Population data: There is no variation at codon 81 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Per Varsome.org, the average coverage at that site in genomes is 28.8x whereas in exomes it is only 4.3x. - |
Atrioventricular septal defect 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 81 of the GATA4 protein (p.Gly81Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GATA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 472775). 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 not expected to disrupt GATA4 protein function with a negative predictive value of 80%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at