rs755862334
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6
The NM_000363.5(TNNI3):āc.55A>Gā(p.Ile19Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000811 in 1,602,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I19L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000363.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNI3 | NM_000363.5 | c.55A>G | p.Ile19Val | missense_variant | 3/8 | ENST00000344887.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNI3 | ENST00000344887.10 | c.55A>G | p.Ile19Val | missense_variant | 3/8 | 1 | NM_000363.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152076Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000351 AC: 8AN: 227684Hom.: 0 AF XY: 0.0000406 AC XY: 5AN XY: 123138
GnomAD4 exome AF: 0.00000689 AC: 10AN: 1450826Hom.: 0 Cov.: 33 AF XY: 0.00000833 AC XY: 6AN XY: 720452
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74274
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 28, 2018 | This sequence change replaces isoleucine with valine at codon 19 of the TNNI3 protein (p.Ile19Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs755862334, ExAC 0.06%). This variant has not been reported in the literature in individuals with TNNI3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 14, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at