rs1555863549
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000363.5(TNNI3):c.403C>T(p.Leu135Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. L135I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000363.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNI3 | NM_000363.5 | c.403C>T | p.Leu135Phe | missense_variant | 7/8 | ENST00000344887.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNI3 | ENST00000344887.10 | c.403C>T | p.Leu135Phe | missense_variant | 7/8 | 1 | NM_000363.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 135 of the TNNI3 protein (p.Leu135Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TNNI3-related conditions. ClinVar contains an entry for this variant (Variation ID: 525033). An algorithm developed specifically for the TNNI3 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 03, 2021 | The p.L135F variant (also known as c.403C>T), located in coding exon 7 of the TNNI3 gene, results from a C to T substitution at nucleotide position 403. The leucine at codon 135 is replaced by phenylalanine, an amino acid with highly similar properties. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at