rs1205923643
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_005257.6(GATA6):c.1223A>G(p.His408Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000444 in 1,577,806 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 (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
GATA6
NM_005257.6 missense
NM_005257.6 missense
Scores
11
3
4
Clinical Significance
Conservation
PhyloP100: 9.11
Genes affected
GATA6 (HGNC:4174): (GATA binding protein 6) This gene is a member of a small family of zinc finger transcription factors that play an important role in the regulation of cellular differentiation and organogenesis during vertebrate development. This gene is expressed during early embryogenesis and localizes to endo- and mesodermally derived cells during later embryogenesis and thereby plays an important role in gut, lung, and heart development. Mutations in this gene are associated with several congenital defects. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.868
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GATA6 | NM_005257.6 | c.1223A>G | p.His408Arg | missense_variant | 3/7 | ENST00000269216.10 | |
GATA6 | XM_047437483.1 | c.1223A>G | p.His408Arg | missense_variant | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GATA6 | ENST00000269216.10 | c.1223A>G | p.His408Arg | missense_variant | 3/7 | 1 | NM_005257.6 | P1 | |
GATA6 | ENST00000581694.1 | c.1223A>G | p.His408Arg | missense_variant | 2/6 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152136Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000537 AC: 1AN: 186356Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 102026
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GnomAD4 exome AF: 0.00000281 AC: 4AN: 1425670Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1AN XY: 706398
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74326
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Atrioventricular septal defect 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 18, 2023 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 408 of the GATA6 protein (p.His408Arg). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with GATA6-related conditions. ClinVar contains an entry for this variant (Variation ID: 540137). 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 expected to disrupt GATA6 protein function with a positive 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Uncertain
D;D
Polyphen
B;B
Vest4
MutPred
Gain of MoRF binding (P = 0.035);Gain of MoRF binding (P = 0.035);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at