rs376621016
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_181486.4(TBX5):c.322C>T(p.Pro108Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,010 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. P108A) has been classified as Uncertain significance.
Frequency
Consequence
NM_181486.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBX5 | NM_181486.4 | c.322C>T | p.Pro108Ser | missense_variant | 4/9 | ENST00000405440.7 | |
TBX5 | NM_000192.3 | c.322C>T | p.Pro108Ser | missense_variant | 4/9 | ||
TBX5 | NM_080717.4 | c.172C>T | p.Pro58Ser | missense_variant | 3/8 | ||
TBX5 | XM_017019912.2 | c.370C>T | p.Pro124Ser | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBX5 | ENST00000405440.7 | c.322C>T | p.Pro108Ser | missense_variant | 4/9 | 1 | NM_181486.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152118Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727246
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152118Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74322
ClinVar
Submissions by phenotype
Aortic valve disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 09, 2021 | In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is present in population databases (rs376621016, ExAC 0.001%) but has not been reported in the literature in individuals with a TBX5-related disease. This sequence change replaces proline with serine at codon 108 of the TBX5 protein (p.Pro108Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at