chr1-74235470-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_015978.3(TNNI3K):ā€‹c.19A>Gā€‹(p.Arg7Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000734 in 1,363,142 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 (ā˜…). Synonymous variant affecting the same amino acid position (i.e. R7R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000073 ( 0 hom. )

Consequence

TNNI3K
NM_015978.3 missense

Scores

6
8
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.15
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, 0.768
BS2
High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TNNI3KNM_015978.3 linkuse as main transcriptc.19A>G p.Arg7Gly missense_variant 1/25 ENST00000326637.8
FPGT-TNNI3KNM_001112808.3 linkuse as main transcriptc.344-632A>G intron_variant
FPGT-TNNI3KNM_001199327.2 linkuse as main transcriptc.344-632A>G intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TNNI3KENST00000326637.8 linkuse as main transcriptc.19A>G p.Arg7Gly missense_variant 1/251 NM_015978.3 P1Q59H18-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000734
AC:
10
AN:
1363142
Hom.:
0
Cov.:
23
AF XY:
0.00000586
AC XY:
4
AN XY:
682400
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:
0.00000867
Gnomad4 OTH exome
AF:
0.0000176
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Atrial conduction disease Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMolecular Genetics, Royal Melbourne HospitalJan 05, 2024This sequence change in TNNI3K is predicted to replace arginine with glycine at codon 7, p.(Arg7Gly). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the L-fucokinase domain. There is a large physicochemical difference between arginine and glycine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.0004% (9/1,038,132 alleles) in the European non-Finnish population. To our knowledge, this variant has not been previously reported in the relevant scientific literature or databases. Computational evidence is uninformative for the missense substitution (REVEL = 0.575). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.20
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.047
T
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.91
D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.77
D
MetaSVM
Uncertain
0.18
D
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
1.0
D;D;D
PROVEAN
Benign
-1.6
N
REVEL
Uncertain
0.57
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.99
D
Vest4
0.80
MutPred
0.30
Loss of MoRF binding (P = 0.0077);
MVP
0.78
ClinPred
0.82
D
GERP RS
3.5
Varity_R
0.25
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.30
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.30
Position offset: 21

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: chr1-74701154; API