NM_003239.5:c.1102_1105delCTGA
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_003239.5(TGFB3):c.1102_1105delCTGA(p.Leu368ThrfsTer18) 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 (★★).
Frequency
Consequence
NM_003239.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TGFB3 | NM_003239.5 | c.1102_1105delCTGA | p.Leu368ThrfsTer18 | frameshift_variant | Exon 7 of 7 | ENST00000238682.8 | NP_003230.1 | |
TGFB3 | NM_001329939.2 | c.1102_1105delCTGA | p.Leu368ThrfsTer18 | frameshift_variant | Exon 8 of 8 | NP_001316868.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
The c.1102_1105delCTGA (p.L368Tfs*18) alteration, located in exon 7 (coding exon 7) of the TGFB3 gene, consists of a deletion of 4 nucleotides from position 1102 to 1105, causing a translational frameshift with a predicted alternate stop codon after 18 amino acids. This alteration occurs at the 3' terminus of theTGFB3 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 10% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as pathogenic. -
Arrhythmogenic right ventricular dysplasia 1;C3810012:Rienhoff syndrome Pathogenic:1
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Rienhoff syndrome Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TGFB3 protein in which other variant(s) (p.Lys407*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 520206). This variant has not been reported in the literature in individuals affected with TGFB3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu368Thrfs*18) in the TGFB3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the TGFB3 protein. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at