chr19-55151835-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4
The NM_000363.5(TNNI3):c.632G>T(p.Ter211Leuext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000363.5 stop_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249570Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135404
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461684Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727146
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74358
ClinVar
Submissions by phenotype
not provided Uncertain:3
The p.X211LeuextX21 variant in TNNI3 has not been previously reported in the literature in individuals with cardiomyopathy but has been reported by other clinical laboratories in ClinVar (Variation ID 181596) and been identified in 0.002% (2/128712) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This stop loss variant changes the normal stop codon to a leucine (Leu) and is predicted to result in a 21 amino acid extension of the protein. The functional impact of this change is unclear. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM4. -
The Stop211Leu variant in the TNNI3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Stop211Leu was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Stop211Leu changes the normal Stop codon to a Leucine codon, leading to the addition of other amino acids at the C-terminal end of the TNNI3 protein. However, in the absence of mRNA studies, the functional consequence of the extension of the protein is unknown. The variant is found in DCM panel(s). -
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Hypertrophic cardiomyopathy Uncertain:2
This sequence change disrupts the translational stop signal of the TNNI3 mRNA. It is expected to extend the length of the TNNI3 protein by 20 additional amino acid residues. This variant is present in population databases (rs730881084, gnomAD 0.002%). 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: 181596). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
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not specified Uncertain:1
Variant summary: TNNI3 c.632G>T (p.X211LeuextX20) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. The variant allele was found at a frequency of 4e-06 in 249570 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.632G>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at