rs1300823855
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_003238.6(TGFB2):āc.362C>Gā(p.Thr121Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,590,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_003238.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFB2 | NM_003238.6 | c.362C>G | p.Thr121Ser | missense_variant | 2/7 | ENST00000366930.9 | |
TGFB2 | NM_001135599.4 | c.446C>G | p.Thr149Ser | missense_variant | 3/8 | ||
TGFB2 | NR_138148.2 | n.1728C>G | non_coding_transcript_exon_variant | 2/7 | |||
TGFB2 | NR_138149.2 | n.1812C>G | non_coding_transcript_exon_variant | 3/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFB2 | ENST00000366930.9 | c.362C>G | p.Thr121Ser | missense_variant | 2/7 | 1 | NM_003238.6 | P1 | |
TGFB2 | ENST00000366929.4 | c.446C>G | p.Thr149Ser | missense_variant | 3/8 | 1 | |||
TGFB2 | ENST00000488793.1 | n.26C>G | non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000411 AC: 1AN: 243522Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 131566
GnomAD4 exome AF: 0.0000118 AC: 17AN: 1438514Hom.: 0 Cov.: 30 AF XY: 0.0000141 AC XY: 10AN XY: 711582
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 10, 2022 | The p.T121S variant (also known as c.362C>G), located in coding exon 2 of the TGFB2 gene, results from a C to G substitution at nucleotide position 362. The threonine at codon 121 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. 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. - |
Loeys-Dietz syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 11, 2023 | This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 121 of the TGFB2 protein (p.Thr121Ser). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with TGFB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 452426). 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 TGFB2 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
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 27, 2018 | The T121S variant in the TGFB2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved by class. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret T121S as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at