rs387906769
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001308093.3(GATA4):c.487C>T(p.Pro163Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000474 in 1,476,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P163R) has been classified as Uncertain significance.
Frequency
Consequence
NM_001308093.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GATA4 | NM_001308093.3 | c.487C>T | p.Pro163Ser | missense_variant | 2/7 | ENST00000532059.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GATA4 | ENST00000532059.6 | c.487C>T | p.Pro163Ser | missense_variant | 2/7 | 1 | NM_001308093.3 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000790 AC: 12AN: 151840Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000729 AC: 6AN: 82342Hom.: 0 AF XY: 0.0000641 AC XY: 3AN XY: 46796
GnomAD4 exome AF: 0.0000445 AC: 59AN: 1324970Hom.: 0 Cov.: 31 AF XY: 0.0000352 AC XY: 23AN XY: 653204
GnomAD4 genome ? AF: 0.0000724 AC: 11AN: 151948Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74278
ClinVar
Submissions by phenotype
Tetralogy of Fallot Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
Atrioventricular septal defect 4 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2010 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 13, 2022 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 163 of the GATA4 protein (p.Pro163Ser). This variant is present in population databases (rs387906769, gnomAD 0.05%). This missense change has been observed in individual(s) with congenital heart defects (PMID: 17643447, 18672102, 20874241, 23626780, 27139165, 28161810, 31513339). ClinVar contains an entry for this variant (Variation ID: 30099). 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. 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:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | GATA4: PP2, PP3, PS3:Supporting, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 11, 2019 | Reported in association with congenital heart defects (Rajagopal et al., 2007; Zhang et al., 2008; Peng et al., 2010; Wang et al., 2013; Wang et al., 2016; Liu et al., 2017); Did not segregate with disease in one family in which all affected family members harbored a variant in the ACTC1 gene (Wang et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21110066, 23626780, 17643447, 18672102, 27139165, 28161810, 31513339) - |
Male infertility with azoospermia or oligozoospermia due to single gene mutation Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Laan Lab, Human Genetics Research Group, University of Tartu | Sep 01, 2023 | - - |
Ventricular septal defect 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2010 | - - |
Testicular anomalies with or without congenital heart disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 15, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS- 3B Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance. For 46,XY disorders of sex development, incomplete penetrance was suggested in PMID:29670578. For cardiac conditions, a large 3 generation family showed high but incomplete penetrance and variable expressivity (PMID:20347099). (N) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (gnomAD (v2.1.1): 0.00006185 (7 Het, 0 Hom). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD: p.(Pro163Arg): 0.00000883 (1 Het, 0 Hom). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif. Located in the GATA-N domain (GATA-type transcription activator, N-terminal) (DECIPHER, NCBI Conserved domains, RCSB-PDB). (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity: p.(Pro163Arg): 1 submission in ClinVar as VUS (Atrioventricular septal defect). (N) 0808 - Previous reports of pathogenicity are conflicting. All publications for this variant relate to cardiac conditions. ClinVar: Conflicting interpretations of pathogenicity: 5 submissions: 4x Pathogenic + 1x VUS, the most recent being VUS. LOVD3: VUS and Likely benign. PMID: 28471988: Meta-studies indicate that this variant is not associated with disease (congenital heart disease). PMID: 23626780: this variant appeared in many controls (cardiac study). (N) 0905 - No segregation evidence has been identified for this variant, in association with a disorder of sex development (DSD). (N) 1002 - Moderate functional evidence supporting abnormal protein function. This variant was shown to have impaired binding with ZFMP2 (PMID: 31513339). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at