1-74236103-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS2_Supporting

The NM_015978.3(TNNI3K):​c.42T>A​(p.Asp14Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000081 in 1,604,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TNNI3K
NM_015978.3 missense, splice_region

Scores

11
7
Splicing: ADA: 0.008184
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.62
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 -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.38949004).
BS2
High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TNNI3KNM_015978.3 linkuse as main transcriptc.42T>A p.Asp14Glu missense_variant, splice_region_variant 2/25 ENST00000326637.8 NP_057062.1
FPGT-TNNI3KNM_001112808.3 linkuse as main transcriptc.345T>A p.Asp115Glu missense_variant, splice_region_variant 4/27 NP_001106279.3
FPGT-TNNI3KNM_001199327.2 linkuse as main transcriptc.345T>A p.Asp115Glu missense_variant, splice_region_variant 4/24 NP_001186256.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TNNI3KENST00000326637.8 linkuse as main transcriptc.42T>A p.Asp14Glu missense_variant, splice_region_variant 2/251 NM_015978.3 ENSP00000322251 P1Q59H18-2

Frequencies

GnomAD3 genomes
AF:
0.0000330
AC:
5
AN:
151558
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000726
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:
0.00633
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
247662
Hom.:
0
AF XY:
0.00000747
AC XY:
1
AN XY:
133926
show subpopulations
Gnomad AFR exome
AF:
0.000188
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000551
AC:
8
AN:
1452390
Hom.:
0
Cov.:
30
AF XY:
0.00000277
AC XY:
2
AN XY:
722582
show subpopulations
Gnomad4 AFR exome
AF:
0.000182
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:
9.04e-7
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.0000330
AC:
5
AN:
151676
Hom.:
0
Cov.:
32
AF XY:
0.0000405
AC XY:
3
AN XY:
74128
show subpopulations
Gnomad4 AFR
AF:
0.0000724
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000340
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

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), LabcorpJul 08, 2022In 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TNNI3K-related conditions. This variant is present in population databases (rs144055969, gnomAD 0.02%). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 14 of the TNNI3K protein (p.Asp14Glu). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Benign
-0.038
T
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.035
.;.;.;.;T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.30
T;T;T;T;T
M_CAP
Benign
0.063
D
MetaRNN
Benign
0.39
T;T;T;T;T
MetaSVM
Uncertain
0.18
D
MutationAssessor
Uncertain
2.1
.;.;.;.;M
MutationTaster
Benign
0.99
D;D;D
PROVEAN
Benign
-0.93
.;N;N;N;N
REVEL
Uncertain
0.50
Sift
Uncertain
0.0060
.;D;D;D;D
Sift4G
Uncertain
0.022
D;D;T;D;D
Polyphen
0.76
.;.;.;.;P
Vest4
0.53
MutPred
0.25
.;.;.;.;Gain of disorder (P = 0.0905);
MVP
0.91
MPC
0.18
ClinPred
0.76
D
GERP RS
4.4
Varity_R
0.45
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0082
dbscSNV1_RF
Benign
0.18
SpliceAI score (max)
0.70
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.70
Position offset: 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: rs144055969; hg19: chr1-74701787; API