NM_015978.3:c.41A>G

Variant names:

• chr1-74236102-A-G
• NM_015978.3:c.41A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015978.3(TNNI3K):​c.41A>G​(p.Asp14Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D14E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNI3K NM_015978.3 missense, splice_region
• Scores: Splicing: ADA: 0.01034
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.37
• Publications: 0 publications found

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]

FPGT-TNNI3K (HGNC:42952): (FPGT-TNNI3K readthrough) Enables protein C-terminus binding activity; protein kinase activity; and troponin I binding activity. Involved in protein phosphorylation and regulation of heart contraction. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3K	NM_015978.3	c.41A>G	p.Asp14Gly	missense_variant, splice_region_variant	Exon 2 of 25	ENST00000326637.8	NP_057062.1
FPGT-TNNI3K	NM_001112808.3	c.344A>G	p.Asp115Gly	missense_variant, splice_region_variant	Exon 4 of 27		NP_001106279.3
FPGT-TNNI3K	NM_001199327.2	c.344A>G	p.Asp115Gly	missense_variant, splice_region_variant	Exon 4 of 24		NP_001186256.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI3K	ENST00000326637.8	c.41A>G	p.Asp14Gly	missense_variant, splice_region_variant	Exon 2 of 25	1	NM_015978.3	ENSP00000322251.3
FPGT-TNNI3K	ENST00000557284.7	c.344A>G	p.Asp115Gly	missense_variant, splice_region_variant	Exon 4 of 27	2		ENSP00000450895.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with TNNI3K-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 14 of the TNNI3K protein (p.Asp14Gly). 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
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	.;.;.;.;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.33	T;T;T;T;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.65	D;D;D;D;D
MetaSVM	Uncertain	-0.016	T
MutationAssessor	Uncertain	2.1	.;.;.;.;M
PhyloP100		5.4
PROVEAN	Benign	-0.84	.;N;N;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	.;D;D;T;D
Sift4G	Benign	0.24	T;T;T;T;D
Polyphen		1.0	.;.;.;.;D
Vest4		0.74
MutPred		0.31		.;.;.;.;Gain of MoRF binding (P = 0.0377);
MVP		0.94
MPC		0.20
ClinPred		0.94	D
GERP RS		4.4
Varity_R		0.57
gMVP		0.75
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.010
dbscSNV1_RF	Benign	0.23
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

Other links and lift over

hg19: chr1-74701786;