chr12-114355927-C-T
Variant summary
Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_181486.4(TBX5):c.1162G>A(p.Glu388Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000452 in 1,613,674 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 (★★).
Frequency
Consequence
NM_181486.4 missense
Scores
Clinical Significance
Conservation
Publications
- Holt-Oram syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
- heart conduction diseaseInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
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ACMG classification
Our verdict: Likely_benign. The variant received -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TBX5 | NM_181486.4 | c.1162G>A | p.Glu388Lys | missense_variant | Exon 9 of 9 | ENST00000405440.7 | NP_852259.1 | |
TBX5 | NM_000192.3 | c.1162G>A | p.Glu388Lys | missense_variant | Exon 9 of 9 | NP_000183.2 | ||
TBX5 | NM_080717.4 | c.1012G>A | p.Glu338Lys | missense_variant | Exon 8 of 8 | NP_542448.1 | ||
TBX5 | XM_017019912.2 | c.1210G>A | p.Glu404Lys | missense_variant | Exon 9 of 9 | XP_016875401.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TBX5 | ENST00000405440.7 | c.1162G>A | p.Glu388Lys | missense_variant | Exon 9 of 9 | 1 | NM_181486.4 | ENSP00000384152.3 | ||
TBX5 | ENST00000310346.8 | c.1162G>A | p.Glu388Lys | missense_variant | Exon 9 of 9 | 1 | ENSP00000309913.4 | |||
TBX5 | ENST00000349716.9 | c.1012G>A | p.Glu338Lys | missense_variant | Exon 8 of 8 | 1 | ENSP00000337723.5 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152194Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000159 AC: 4AN: 250880 AF XY: 0.0000147 show subpopulations
GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461480Hom.: 0 Cov.: 33 AF XY: 0.0000468 AC XY: 34AN XY: 727060 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74336 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Aortic valve disease 2 Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 388 of the TBX5 protein (p.Glu388Lys). This variant is present in population databases (rs139371720, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 31983221). This variant is also known as chr12:g.114793732C>T. ClinVar contains an entry for this variant (Variation ID: 411098). 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 TBX5 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:1
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Cardiovascular phenotype Uncertain:1
The p.E388K variant (also known as c.1162G>A), located in coding exon 8 of the TBX5 gene, results from a G to A substitution at nucleotide position 1162. The glutamic acid at codon 388 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort with limited clinical details (Mazzarotto F et al. Circulation, 2020 02;141:387-398). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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