1-74235474-C-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_015978.3(TNNI3K):c.23C>A(p.Pro8Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000294 in 1,359,278 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 (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000029 ( 0 hom. )
Consequence
TNNI3K
NM_015978.3 missense
NM_015978.3 missense
Scores
8
5
5
Clinical Significance
Conservation
PhyloP100: 4.49
Genes affected
TNNI3K (HGNC:19661): (TNNI3 interacting kinase) This gene encodes a protein that belongs to the MAP kinase kinase kinase (MAPKKK) family of protein kinases. The protein contains ankyrin repeat, protein kinase and serine-rich domains and is thought to play a role in cardiac physiology. [provided by RefSeq, Sep 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.802
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TNNI3K | NM_015978.3 | c.23C>A | p.Pro8Gln | missense_variant | 1/25 | ENST00000326637.8 | NP_057062.1 | |
FPGT-TNNI3K | NM_001112808.3 | c.344-628C>A | intron_variant | NP_001106279.3 | ||||
FPGT-TNNI3K | NM_001199327.2 | c.344-628C>A | intron_variant | NP_001186256.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TNNI3K | ENST00000326637.8 | c.23C>A | p.Pro8Gln | missense_variant | 1/25 | 1 | NM_015978.3 | ENSP00000322251 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000442 AC: 1AN: 226484Hom.: 0 AF XY: 0.00000810 AC XY: 1AN XY: 123458
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GnomAD4 exome AF: 0.00000294 AC: 4AN: 1359278Hom.: 0 Cov.: 23 AF XY: 0.00000294 AC XY: 2AN XY: 680736
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 03, 2023 | This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 8 of the TNNI3K protein (p.Pro8Gln). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with TNNI3K-related conditions. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D;D;D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of MoRF binding (P = 0.0316);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at