rs925224125
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM5PP3_ModerateBS2
The NM_003239.5(TGFB3):c.464G>A(p.Arg155Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,868 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. R155W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003239.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFB3 | NM_003239.5 | c.464G>A | p.Arg155Gln | missense_variant | 2/7 | ENST00000238682.8 | |
TGFB3 | NM_001329939.2 | c.464G>A | p.Arg155Gln | missense_variant | 3/8 | ||
TGFB3 | NM_001329938.2 | c.464G>A | p.Arg155Gln | missense_variant | 2/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFB3 | ENST00000238682.8 | c.464G>A | p.Arg155Gln | missense_variant | 2/7 | 1 | NM_003239.5 | P1 | |
TGFB3-AS1 | ENST00000553732.1 | downstream_gene_variant | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251366Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135864
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727236
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 1;C3810012:Rienhoff syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | TGFB3 NM_003239.4 exon 2 p.Arg155Gln (c.464G>A): This variant has not been reported in the literature but is present in 0.0003% (1/251366) of total alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/14-76437950-C-T). This variant is present in ClinVar (Variation ID:575813). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2020 | Has not been previously published as pathogenic or benign to our knowledge; 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 - |
Rienhoff syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 155 of the TGFB3 protein (p.Arg155Gln). 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. This variant disrupts the p.Arg155 amino acid residue in TGFB3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31898322, 32897753; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 TGFB3 protein function. ClinVar contains an entry for this variant (Variation ID: 575813). This missense change has been observed in individual(s) with clinical features of Loeys-Dietz syndrome (Invitae). This variant is present in population databases (no rsID available, gnomAD no frequency). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at