chr7-35202464-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_001077653.2(TBX20):c.1310G>A(p.Arg437His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,600,790 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R437L) has been classified as Likely benign.
Frequency
Consequence
NM_001077653.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBX20 | NM_001077653.2 | c.1310G>A | p.Arg437His | missense_variant | 8/8 | ENST00000408931.4 | |
TBX20 | XM_017012456.2 | c.713G>A | p.Arg238His | missense_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBX20 | ENST00000408931.4 | c.1310G>A | p.Arg437His | missense_variant | 8/8 | 1 | NM_001077653.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000140 AC: 21AN: 149844Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000103 AC: 24AN: 233228Hom.: 0 AF XY: 0.0000714 AC XY: 9AN XY: 126120
GnomAD4 exome AF: 0.000283 AC: 411AN: 1450946Hom.: 0 Cov.: 33 AF XY: 0.000277 AC XY: 200AN XY: 720794
GnomAD4 genome AF: 0.000140 AC: 21AN: 149844Hom.: 0 Cov.: 31 AF XY: 0.0000823 AC XY: 6AN XY: 72912
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 31, 2023 | Identified in a significant number of both affected individuals and ethnically-matched controls in published literature (Qian et al., 2008); 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: 19074289, 29089047) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 437 of the TBX20 protein (p.Arg437His). This variant is present in population databases (rs375484585, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TBX20-related conditions. ClinVar contains an entry for this variant (Variation ID: 519058). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Atrial septal defect 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 09, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 23, 2023 | The p.R437H variant (also known as c.1310G>A), located in coding exon 8 of the TBX20 gene, results from a G to A substitution at nucleotide position 1310. The arginine at codon 437 is replaced by histidine, an amino acid with highly similar properties. In a study including patient cohorts with dilated cardiomyopathy (DCM) or congenital heart defects, this amino acid variant was reported in numerous patients in each cohort in addition to over 100 control subjects (Qian L et al. Proc Natl Acad Sci U.S.A. 2008;105(50):19833-8). This alteration has also been identified in a cohort of individuals undergoing whole exome sequencing for diverse clinical indications (Li AH et al. Genome Med, 2017 10;9:95). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at