rs755070814
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2
The NM_003242.6(TGFBR2):c.1643C>T(p.Ser548Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,948 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S548S) has been classified as Likely benign.
Frequency
Consequence
NM_003242.6 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 |
---|---|---|---|---|---|---|---|
TGFBR2 | NM_003242.6 | c.1643C>T | p.Ser548Leu | missense_variant | 7/7 | ENST00000295754.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFBR2 | ENST00000295754.10 | c.1643C>T | p.Ser548Leu | missense_variant | 7/7 | 1 | NM_003242.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152090Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251188Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135740
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727234
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152090Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74294
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 11, 2023 | The p.S548L variant (also known as c.1643C>T), located in coding exon 7 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1643. The serine at codon 548 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a spontaneous coronary artery dissection cohort (Verstraeten A et al. Circulation, 2020 Sep;142:1021-1024). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 18, 2023 | This missense variant replaces serine with leucine at codon 548 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with spontaneous coronary artery dissection and renal fibromuscular dysplasia (PMID: 32897753). This variant has been identified in 4/251188 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 28, 2023 | 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. 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 expected to disrupt TGFBR2 protein function. ClinVar contains an entry for this variant (Variation ID: 408441). This variant is also known as c.1718C>T; p.Ser573Leu. This missense change has been observed in individual(s) with TGFBR2-related conditions (PMID: 32897753). This variant is present in population databases (rs755070814, gnomAD 0.01%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 548 of the TGFBR2 protein (p.Ser548Leu). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 03, 2021 | Variant summary: TGFBR2 c.1643C>T (p.Ser548Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251188 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1643C>T in individuals affected with Loeys-Dietz Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Malignant tumor of esophagus;C1860896:Colorectal cancer, hereditary nonpolyposis, type 6;C2674574:Loeys-Dietz syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 07, 2021 | - - |
Loeys-Dietz syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 23, 2023 | This missense variant replaces serine with leucine at codon 573 of the TGFBR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/251188 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 06, 2021 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at