1-74236118-A-T

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

Scores

2
10
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.06
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 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
TNNI3KNM_015978.3 linkuse as main transcriptc.57A>T p.Lys19Asn missense_variant 2/25 ENST00000326637.8
FPGT-TNNI3KNM_001112808.3 linkuse as main transcriptc.360A>T p.Lys120Asn missense_variant 4/27
FPGT-TNNI3KNM_001199327.2 linkuse as main transcriptc.360A>T p.Lys120Asn missense_variant 4/24

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TNNI3KENST00000326637.8 linkuse as main transcriptc.57A>T p.Lys19Asn missense_variant 2/251 NM_015978.3 P1Q59H18-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000275
AC:
4
AN:
1454280
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
723454
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:
0.00000361
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), LabcorpMar 07, 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. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Uncertain
0.038
T
BayesDel_noAF
Benign
-0.18
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.043
.;.;.;.;T
Eigen
Uncertain
0.29
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.91
D;D;D;D;D
M_CAP
Benign
0.059
D
MetaRNN
Uncertain
0.49
T;T;T;T;T
MetaSVM
Benign
-0.34
T
MutationAssessor
Uncertain
2.1
.;.;.;.;M
MutationTaster
Benign
0.99
D;D;D
PROVEAN
Benign
-1.3
.;N;N;N;N
REVEL
Uncertain
0.48
Sift
Pathogenic
0.0
.;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D
Polyphen
1.0
.;.;.;.;D
Vest4
0.59
MutPred
0.41
.;.;.;.;Loss of methylation at K19 (P = 0.005);
MVP
0.85
MPC
0.20
ClinPred
0.97
D
GERP RS
2.9
Varity_R
0.48
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: chr1-74701802; API