rs911752926
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2
The NM_005257.6(GATA6):c.775G>A(p.Val259Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,175,990 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V259V) has been classified as Likely benign.
Frequency
Consequence
NM_005257.6 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GATA6 | NM_005257.6 | c.775G>A | p.Val259Ile | missense_variant | 2/7 | ENST00000269216.10 | |
GATA6 | XM_047437483.1 | c.775G>A | p.Val259Ile | missense_variant | 2/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GATA6 | ENST00000269216.10 | c.775G>A | p.Val259Ile | missense_variant | 2/7 | 1 | NM_005257.6 | P1 | |
GATA6 | ENST00000581694.1 | c.775G>A | p.Val259Ile | missense_variant | 1/6 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000107 AC: 16AN: 149428Hom.: 1 Cov.: 32
GnomAD4 exome AF: 0.0000604 AC: 62AN: 1026456Hom.: 1 Cov.: 29 AF XY: 0.0000723 AC XY: 35AN XY: 483796
GnomAD4 genome ? AF: 0.000107 AC: 16AN: 149534Hom.: 1 Cov.: 32 AF XY: 0.000165 AC XY: 12AN XY: 72934
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 13, 2021 | The c.775G>A (p.V259I) alteration is located in exon 2 (coding exon 1) of the GATA6 gene. This alteration results from a G to A substitution at nucleotide position 775, causing the valine (V) at amino acid position 259 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Atrioventricular septal defect 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2023 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 259 of the GATA6 protein (p.Val259Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This missense change has been observed in individual(s) with congenital heart disease (PMID: 34493817, 36525927). ClinVar contains an entry for this variant (Variation ID: 540130). 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 GATA6 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. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | GATA6: PP3, BS1, BS2 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at