rs1555360362
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The ENST00000238682.8(TGFB3):c.916del(p.Tyr306ThrfsTer63) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
TGFB3
ENST00000238682.8 frameshift
ENST00000238682.8 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.07
Genes affected
TGFB3 (HGNC:11769): (transforming growth factor beta 3) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. This protein is involved in embryogenesis and cell differentiation, and may play a role in wound healing. Mutations in this gene are a cause of aortic aneurysms and dissections, as well as familial arrhythmogenic right ventricular dysplasia 1. [provided by RefSeq, Aug 2016]
IFT43 (HGNC:29669): (intraflagellar transport 43) This gene encodes a subunit of the intraflagellar transport complex A (IFT-A). IFT-A is a multiprotein complex that plays an important role in cilia assembly and maintenance by mediating retrograde ciliary transport. Mutations in this gene are a cause of cranioectodermal dysplasia-3 (CED3), also known as Sensenbrenner syndrome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-75963325-TA-T is Pathogenic according to our data. Variant chr14-75963325-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 543951.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TGFB3 | NM_003239.5 | c.916del | p.Tyr306ThrfsTer63 | frameshift_variant | 5/7 | ENST00000238682.8 | NP_003230.1 | |
TGFB3 | NM_001329939.2 | c.916del | p.Tyr306ThrfsTer63 | frameshift_variant | 6/8 | NP_001316868.1 | ||
TGFB3 | NM_001329938.2 | c.916del | p.Tyr306ThrfsTer23 | frameshift_variant | 5/5 | NP_001316867.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TGFB3 | ENST00000238682.8 | c.916del | p.Tyr306ThrfsTer63 | frameshift_variant | 5/7 | 1 | NM_003239.5 | ENSP00000238682 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Rienhoff syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 27, 2018 | 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. The C-terminal portion of the TGFB3 protein encodes the mature peptide domain (PMID: 22943793, 25835445, 1631557). Variants within this domain (p.Tyr365*, p.Leu386Argfs*21, and p.Cys409Tyr) have been reported in individuals affected with aortic aneurisms and dissections (PMID: 25835445) or Reinhoff syndrome (PMID: 23824657). This suggests that this region is critical for TGFB3 protein function. This variant has not been reported in the literature in individuals with TGFB3-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the TGFB3 gene (p.Tyr306Thrfs*63). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 107 amino acids of the TGFB3 protein. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at