rs1057521530
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_000363.5(TNNI3):c.493G>T(p.Glu165Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,018 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E165E) has been classified as Likely benign.
Frequency
Consequence
NM_000363.5 stop_gained
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.493G>T | p.Glu165Ter | stop_gained | 7/8 | ENST00000344887.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNI3 | ENST00000344887.10 | c.493G>T | p.Glu165Ter | stop_gained | 7/8 | 1 | NM_000363.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152018Hom.: 0 Cov.: 31
GnomAD4 exome Cov.: 32
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152018Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74256
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 15, 2016 | The likely pathogenic E165X variant in the TNNI3 gene has not been reported as a pathogenic variant or as a benign variant to our knowledge. This variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. E165X is predicted to cause loss of normal protein function by protein truncation (loss of the last 46 amino acids). However, no nonsense variants in the TNNI3 gene have been reported in HGMD (Stenson et al., 2014). Most of the pathogenic variants in TNNI3 reported in HGMD are missense substitutions that affect the calcium sensitivity of contraction. While haploinsufficiency is not a well-established mechanism of disease for the TNNI3 gene, other truncation variants have been reported in HGMD (Stenson et al., 2014). Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required. - |
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 23, 2023 | This variant changes 1 nucleotide in exon 7 of the TNNI3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24793961, 29875424). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function TNNI3 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. The 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 | Dec 19, 2019 | This sequence change creates a premature translational stop signal (p.Glu165*) in the TNNI3 gene. It is expected to result in an absent or disrupted protein product. 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. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TNNI3 cause disease. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 24793961). ClinVar contains an entry for this variant (Variation ID: 383149). This variant is not present in population databases (ExAC no frequency). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at