chr1-74235452-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_015978.3(TNNI3K):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. 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)

Consequence

TNNI3K
NM_015978.3 start_lost

Scores

7
6
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.02
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 Pathogenic. Variant got 10 ACMG points.

PVS1
Start lost variant, no new inframe start found.
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.1A>G p.Met1? start_lost 1/25 ENST00000326637.8
FPGT-TNNI3KNM_001112808.3 linkuse as main transcriptc.344-650A>G intron_variant
FPGT-TNNI3KNM_001199327.2 linkuse as main transcriptc.344-650A>G intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TNNI3KENST00000326637.8 linkuse as main transcriptc.1A>G p.Met1? start_lost 1/251 NM_015978.3 P1Q59H18-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
24
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 testingInvitaeNov 01, 2023This sequence change affects the initiator methionine of the TNNI3K mRNA. The next in-frame methionine is located at codon 88. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.039
T
Eigen
Uncertain
0.66
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.81
D
MetaSVM
Uncertain
0.066
D
MutationTaster
Benign
1.0
D;D;D
PROVEAN
Benign
-1.1
N
REVEL
Uncertain
0.56
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.92
P
Vest4
0.87
MutPred
0.49
Loss of MoRF binding (P = 0.1182);
MVP
0.83
ClinPred
0.78
D
GERP RS
5.9
Varity_R
0.83
gMVP
0.61

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: chr1-74701136; API