chr1-74235486-G-A
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_015978.3(TNNI3K):c.35G>A(p.Cys12Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 1,455,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
TNNI3K
NM_015978.3 missense
NM_015978.3 missense
Scores
9
4
5
Clinical Significance
Conservation
PhyloP100: 5.95
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 Likely_benign. Variant got -3 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.83
BS2
High AC in GnomAdExome4 at 17 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNI3K | NM_015978.3 | c.35G>A | p.Cys12Tyr | missense_variant | 1/25 | ENST00000326637.8 | |
FPGT-TNNI3K | NM_001112808.3 | c.344-616G>A | intron_variant | ||||
FPGT-TNNI3K | NM_001199327.2 | c.344-616G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNI3K | ENST00000326637.8 | c.35G>A | p.Cys12Tyr | missense_variant | 1/25 | 1 | NM_015978.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151510Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000903 AC: 2AN: 221454Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 120916
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GnomAD4 exome AF: 0.0000130 AC: 17AN: 1303654Hom.: 0 Cov.: 22 AF XY: 0.00000763 AC XY: 5AN XY: 655678
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151510Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 73998
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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 | Jan 19, 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) performed at Invitae indicates that this missense variant is not expected to disrupt TNNI3K protein function. ClinVar contains an entry for this variant (Variation ID: 1460658). This variant has not been reported in the literature in individuals affected with TNNI3K-related conditions. This variant is present in population databases (rs200469447, gnomAD 0.002%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 12 of the TNNI3K protein (p.Cys12Tyr). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D;D;D
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at