rs868258653
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_003239.5(TGFB3):c.463C>T(p.Arg155Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,074 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R155Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_003239.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFB3 | NM_003239.5 | c.463C>T | p.Arg155Trp | missense_variant | 2/7 | ENST00000238682.8 | |
TGFB3 | NM_001329939.2 | c.463C>T | p.Arg155Trp | missense_variant | 3/8 | ||
TGFB3 | NM_001329938.2 | c.463C>T | p.Arg155Trp | missense_variant | 2/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFB3 | ENST00000238682.8 | c.463C>T | p.Arg155Trp | missense_variant | 2/7 | 1 | NM_003239.5 | P1 | |
TGFB3-AS1 | ENST00000553732.1 | downstream_gene_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152230Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461844Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727208
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74378
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 14, 2021 | The p.R155W variant (also known as c.463C>T), located in coding exon 2 of the TGFB3 gene, results from a C to T substitution at nucleotide position 463. The arginine at codon 155 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in affected individuals with features of Loeys-Dietz syndrome, including aortic dissection, tortuosity of the vertebral arteries, bifid uvula, and/ or other connective tissue disease findings (Verstraeten A et al. Circulation, 2020 09;142:1021-1024; Marsili L et al. Clin Genet, 2020 05;97:723-730). Based on internal structural analysis, p.R155W decreases the structure stability (Ambry internal data; Zhao B et al. J Biol Chem, 2018 02;293:1579-1589). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Rienhoff syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 155 of the TGFB3 protein (p.Arg155Trp). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg155 amino acid residue in TGFB3. Other variant(s) that disrupt this residue have been observed in individuals with TGFB3-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 543955). This missense change has been observed in individuals with clinical features of TGFB3-related conditions (PMID: 31898322, 32897753; Invitae). This variant is not present in population databases (gnomAD no frequency). - |
Arrhythmogenic right ventricular dysplasia 1;C3810012:Rienhoff syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 12, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 15, 2022 | Reported in patients with TAAD, coronary artery dissection, and/or other connective tissue disorder features that overlap with those observed in Loeys-Dietz syndrome (Marsili et al., 2020; Verstraeten et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32897753, 31898322) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at