1-74236118-A-T
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_015978.3(TNNI3K):c.57A>T(p.Lys19Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,280 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
TNNI3K
NM_015978.3 missense
NM_015978.3 missense
Scores
2
10
6
Clinical Significance
Conservation
PhyloP100: 2.06
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 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNI3K | NM_015978.3 | c.57A>T | p.Lys19Asn | missense_variant | 2/25 | ENST00000326637.8 | |
FPGT-TNNI3K | NM_001112808.3 | c.360A>T | p.Lys120Asn | missense_variant | 4/27 | ||
FPGT-TNNI3K | NM_001199327.2 | c.360A>T | p.Lys120Asn | missense_variant | 4/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNI3K | ENST00000326637.8 | c.57A>T | p.Lys19Asn | missense_variant | 2/25 | 1 | NM_015978.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1454280Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 723454
GnomAD4 exome
AF:
AC:
4
AN:
1454280
Hom.:
Cov.:
30
AF XY:
AC XY:
1
AN XY:
723454
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
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 | Invitae | Mar 07, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TNNI3K protein function. This variant has not been reported in the literature in individuals affected with TNNI3K-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 19 of the TNNI3K protein (p.Lys19Asn). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;.;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;.;.;.;M
MutationTaster
Benign
D;D;D
PROVEAN
Benign
.;N;N;N;N
REVEL
Uncertain
Sift
Pathogenic
.;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
1.0
.;.;.;.;D
Vest4
MutPred
0.41
.;.;.;.;Loss of methylation at K19 (P = 0.005);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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
Publications
No publications associated with this variant yet.