1-74235488-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015978.3(TNNI3K):ā€‹c.37A>Gā€‹(p.Thr13Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,289,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000062 ( 0 hom. )

Consequence

TNNI3K
NM_015978.3 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.48
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.18396908).
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TNNI3KNM_015978.3 linkuse as main transcriptc.37A>G p.Thr13Ala missense_variant 1/25 ENST00000326637.8 NP_057062.1
FPGT-TNNI3KNM_001112808.3 linkuse as main transcriptc.344-614A>G intron_variant NP_001106279.3
FPGT-TNNI3KNM_001199327.2 linkuse as main transcriptc.344-614A>G intron_variant NP_001186256.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TNNI3KENST00000326637.8 linkuse as main transcriptc.37A>G p.Thr13Ala missense_variant 1/251 NM_015978.3 ENSP00000322251 P1Q59H18-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000620
AC:
8
AN:
1289304
Hom.:
0
Cov.:
21
AF XY:
0.00000308
AC XY:
2
AN XY:
649090
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000821
Gnomad4 OTH exome
AF:
0.00
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), LabcorpDec 04, 2023This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 13 of the TNNI3K protein (p.Thr13Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TNNI3K-related conditions. 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) performed at Invitae indicates that this missense variant is not expected to disrupt TNNI3K protein function with a negative predictive value of 80%. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Benign
-0.017
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
19
DANN
Benign
0.96
DEOGEN2
Benign
0.026
T
Eigen
Benign
-0.088
Eigen_PC
Benign
0.088
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.76
T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
-1.2
N
MutationTaster
Benign
0.80
D;D;D
PROVEAN
Benign
-0.12
N
REVEL
Benign
0.27
Sift
Benign
0.34
T
Sift4G
Benign
0.52
T
Polyphen
0.0
B
Vest4
0.48
MutPred
0.29
Loss of phosphorylation at T13 (P = 0.0554);
MVP
0.60
ClinPred
0.31
T
GERP RS
4.8
Varity_R
0.053
gMVP
0.50

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1451279328; hg19: chr1-74701172; API