1-74236104-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015978.3(TNNI3K):​c.43G>A​(p.Glu15Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TNNI3K
NM_015978.3 missense, splice_region

Scores

5
10
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.87
Variant links:
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 Protein UniProt
TNNI3KNM_015978.3 linkuse as main transcriptc.43G>A p.Glu15Lys missense_variant, splice_region_variant 2/25 ENST00000326637.8 NP_057062.1
FPGT-TNNI3KNM_001112808.3 linkuse as main transcriptc.346G>A p.Glu116Lys missense_variant, splice_region_variant 4/27 NP_001106279.3
FPGT-TNNI3KNM_001199327.2 linkuse as main transcriptc.346G>A p.Glu116Lys missense_variant, splice_region_variant 4/24 NP_001186256.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TNNI3KENST00000326637.8 linkuse as main transcriptc.43G>A p.Glu15Lys missense_variant, splice_region_variant 2/251 NM_015978.3 ENSP00000322251 P1Q59H18-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 28, 2023In 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. 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. 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 glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 15 of the TNNI3K protein (p.Glu15Lys). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.030
.;.;.;.;T
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.94
D;D;D;D;D
M_CAP
Uncertain
0.087
D
MetaRNN
Uncertain
0.62
D;D;D;D;D
MetaSVM
Uncertain
-0.062
T
MutationAssessor
Uncertain
2.1
.;.;.;.;M
MutationTaster
Benign
1.0
D;D;D
PROVEAN
Benign
-0.94
.;N;N;N;N
REVEL
Uncertain
0.43
Sift
Pathogenic
0.0
.;D;D;D;D
Sift4G
Uncertain
0.015
D;D;T;T;D
Polyphen
1.0
.;.;.;.;D
Vest4
0.74
MutPred
0.37
.;.;.;.;Gain of MoRF binding (P = 0.0026);
MVP
0.81
MPC
0.19
ClinPred
0.98
D
GERP RS
4.6
Varity_R
0.61
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-74701788; COSMIC: COSV58565670; COSMIC: COSV58565670; API