rs730881072
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000363.5(TNNI3):c.451G>A(p.Ala151Thr) 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 (★★).
Frequency
Genomes: not found (cov: 31)
Consequence
TNNI3
NM_000363.5 missense
NM_000363.5 missense
Scores
11
8
1
Clinical Significance
Conservation
PhyloP100: 7.82
Genes affected
TNNI3 (HGNC:11947): (troponin I3, cardiac type) Troponin I (TnI), along with troponin T (TnT) and troponin C (TnC), is one of 3 subunits that form the troponin complex of the thin filaments of striated muscle. TnI is the inhibitory subunit; blocking actin-myosin interactions and thereby mediating striated muscle relaxation. The TnI subfamily contains three genes: TnI-skeletal-fast-twitch, TnI-skeletal-slow-twitch, and TnI-cardiac. This gene encodes the TnI-cardiac protein and is exclusively expressed in cardiac muscle tissues. Mutations in this gene cause familial hypertrophic cardiomyopathy type 7 (CMH7) and familial restrictive cardiomyopathy (RCM). Troponin I is useful in making a diagnosis of heart failure, and of ischemic heart disease. An elevated level of troponin is also now used as indicator of acute myocardial injury in patients hospitalized with moderate/severe Coronavirus Disease 2019 (COVID-19). Such elevation has also been associated with higher risk of mortality in cardiovascular disease patients hospitalized due to COVID-19. [provided by RefSeq, Aug 2020]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000363.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.926
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNI3 | NM_000363.5 | c.451G>A | p.Ala151Thr | missense_variant | 7/8 | ENST00000344887.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNI3 | ENST00000344887.10 | c.451G>A | p.Ala151Thr | missense_variant | 7/8 | 1 | NM_000363.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2020 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 181581; Landrum et al., 2016) - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 151 of the TNNI3 protein (p.Ala151Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 181581). 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 disruptive. 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 | Oct 31, 2019 | The p.A151T variant (also known as c.451G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 451. The alanine at codon 151 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
CardioboostCm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
T;T
Polyphen
D;.
Vest4
MutPred
Gain of phosphorylation at A151 (P = 0.0539);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at