rs759523214
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_000363.5(TNNI3):c.250G>T(p.Glu84*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,556 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 (★). Variant results in nonsense mediated mRNA decay.
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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TNNI3 | ENST00000344887.10 | c.250G>T | p.Glu84* | stop_gained | Exon 5 of 8 | 1 | NM_000363.5 | ENSP00000341838.5 | ||
ENSG00000267110 | ENST00000587871.1 | n.*352G>T | non_coding_transcript_exon_variant | Exon 8 of 9 | 5 | ENSP00000473050.1 | ||||
ENSG00000267110 | ENST00000587871.1 | n.*352G>T | 3_prime_UTR_variant | Exon 8 of 9 | 5 | ENSP00000473050.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460398Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726554
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74336
ClinVar
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
The p.E84* variant (also known as c.250G>T), located in coding exon 5 of the TNNI3 gene, results from a G to T substitution at nucleotide position 250. This changes the amino acid from a glutamic acid to a stop codon within coding exon 5. This alteration was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), Exome Aggregation Consortium (ExAC), and 1000 Genomes Project. In the ESP, this variant was not observed in 5481 samples (10962 alleles) with coverage at this position. This alteration is expected to result in either premature protein truncation or haploinsufficiency by nonsense-mediated mRNA decay. Haploinsufficiency for TNNI3 has not been clearly established as a mechanism of disease, however, as most mutations in troponin proteins are thought to alter the calcium sensitivity of cardiomyocyte contraction. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at