chr1-74235486-G-A

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

Scores

9
4
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.95
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 -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
TNNI3KNM_015978.3 linkuse as main transcriptc.35G>A p.Cys12Tyr missense_variant 1/25 ENST00000326637.8
FPGT-TNNI3KNM_001112808.3 linkuse as main transcriptc.344-616G>A intron_variant
FPGT-TNNI3KNM_001199327.2 linkuse as main transcriptc.344-616G>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TNNI3KENST00000326637.8 linkuse as main transcriptc.35G>A p.Cys12Tyr missense_variant 1/251 NM_015978.3 P1Q59H18-2

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151510
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000148
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000903
AC:
2
AN:
221454
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
120916
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000189
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
17
AN:
1303654
Hom.:
0
Cov.:
22
AF XY:
0.00000763
AC XY:
5
AN XY:
655678
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:
0.0000162
Gnomad4 OTH exome
AF:
0.0000183
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151510
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
73998
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000148
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
ExAC
AF:
0.0000165
AC:
2

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 testingInvitaeJan 19, 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) 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
T
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.058
D
MetaRNN
Pathogenic
0.83
D
MetaSVM
Uncertain
0.39
D
MutationAssessor
Benign
1.5
L
MutationTaster
Benign
1.0
D;D;D
PROVEAN
Benign
-2.3
N
REVEL
Pathogenic
0.66
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0050
D
Polyphen
1.0
D
Vest4
0.82
MVP
0.74
ClinPred
0.84
D
GERP RS
5.9
Varity_R
0.72
gMVP
0.56

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: rs200469447; hg19: chr1-74701170; API