rs776035548
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong
The NM_000363.5(TNNI3):c.278T>C(p.Leu93Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,612,606 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L93L) has been classified as Likely benign.
Frequency
Consequence
NM_000363.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNI3 | NM_000363.5 | c.278T>C | p.Leu93Pro | missense_variant | 5/8 | ENST00000344887.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNI3 | ENST00000344887.10 | c.278T>C | p.Leu93Pro | missense_variant | 5/8 | 1 | NM_000363.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000825 AC: 2AN: 242490Hom.: 0 AF XY: 0.00000751 AC XY: 1AN XY: 133148
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1460522Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 726604
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74290
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 03, 2023 | This missense variant replaces leucine with proline at codon 93 of the TNNI3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/242490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2023 | An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 525020). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 31737537). This variant is present in population databases (rs776035548, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 93 of the TNNI3 protein (p.Leu93Pro). 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 12, 2019 | This missense variant replaces leucine with proline at codon 93 of the TNNI3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/242490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at