1-74235488-A-G

Variant names:

• chr1-74235488-A-G
• rs1451279328
• NM_015978.3:c.37A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015978.3(TNNI3K):​c.37A>G​(p.Thr13Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,289,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TNNI3K NM_015978.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.48
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18396908).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3K	NM_015978.3	c.37A>G	p.Thr13Ala	missense_variant	Exon 1 of 25	ENST00000326637.8	NP_057062.1
FPGT-TNNI3K	NM_001112808.3	c.344-614A>G		intron_variant	Intron 3 of 26		NP_001106279.3
FPGT-TNNI3K	NM_001199327.2	c.344-614A>G		intron_variant	Intron 3 of 23		NP_001186256.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI3K	ENST00000326637.8	c.37A>G	p.Thr13Ala	missense_variant	Exon 1 of 25	1	NM_015978.3	ENSP00000322251.3
FPGT-TNNI3K	ENST00000557284.7	c.344-614A>G		intron_variant	Intron 3 of 26	2		ENSP00000450895.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 221420 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000620 AC: 8 AN: 1289304 Hom.: 0 Cov.: 21 AF XY: 0.00000308 AC XY: 2 AN XY: 649090

African (AFR) AF: 0.00 AC: 0 AN: 28086

American (AMR) AF: 0.00 AC: 0 AN: 34864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24344

East Asian (EAS) AF: 0.00 AC: 0 AN: 37392

South Asian (SAS) AF: 0.00 AC: 0 AN: 77292

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5372

European-Non Finnish (NFE) AF: 0.00000821 AC: 8 AN: 974782

Other (OTH) AF: 0.00 AC: 0 AN: 54156

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 13 of the TNNI3K protein (p.Thr13Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TNNI3K-related conditions. 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 with a negative predictive value of 80%. 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	Benign	0.23
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.088
Eigen_PC	Benign	0.088
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.2	N
PhyloP100		5.5
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.27
Sift	Benign	0.34	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.48
MutPred		0.29		Loss of phosphorylation at T13 (P = 0.0554);
MVP		0.60
ClinPred		0.31	T
GERP RS		4.8
PromoterAI		-0.013	Neutral
Varity_R		0.053
gMVP		0.50
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1451279328; hg19: chr1-74701172;