19-55154151-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The NM_000363.5(TNNI3):c.428C>A(p.Thr143Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TNNI3
NM_000363.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8

Conservation

PhyloP100: 3.12

Variant links:

Genes affected

TNNI3 (HGNC:11947): (troponin I3, cardiac type) Troponin I (TnI), along with troponin T (TnT) and troponin C (TnC), is one of 3 subunits that form the troponin complex of the thin filaments of striated muscle. TnI is the inhibitory subunit; blocking actin-myosin interactions and thereby mediating striated muscle relaxation. The TnI subfamily contains three genes: TnI-skeletal-fast-twitch, TnI-skeletal-slow-twitch, and TnI-cardiac. This gene encodes the TnI-cardiac protein and is exclusively expressed in cardiac muscle tissues. Mutations in this gene cause familial hypertrophic cardiomyopathy type 7 (CMH7) and familial restrictive cardiomyopathy (RCM). Troponin I is useful in making a diagnosis of heart failure, and of ischemic heart disease. An elevated level of troponin is also now used as indicator of acute myocardial injury in patients hospitalized with moderate/severe Coronavirus Disease 2019 (COVID-19). Such elevation has also been associated with higher risk of mortality in cardiovascular disease patients hospitalized due to COVID-19. [provided by RefSeq, Aug 2020]

TNNI3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a helix (size 19) in uniprot entity TNNI3_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000363.5

BP4

Computational evidence support a benign effect (MetaRNN=0.3508703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3	NM_000363.5 link	c.428C>A	p.Thr143Asn	missense_variant	Exon 7 of 8	ENST00000344887.10	NP_000354.4	P19429Q6FGX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10 link	c.428C>A	p.Thr143Asn	missense_variant	Exon 7 of 8	1	NM_000363.5	ENSP00000341838.5		P19429

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000362

AC:

AN:

248930

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135100

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:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461094

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726846

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:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152028

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Jan 16, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 17010989, 26526134, 23690394, 25228707, 30731207, 26936621, 21310275, 17872964, 15774859, 7592712) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 02, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr143Asn variant in TNNI3 has been reported by our laboratory in 3 individuals with early onset HCM, two of whom had an additional pathogenic variant in 1 or more genes (LMM data, Walsh 2017 PMID: 27532257, Bales 2016 PMID: 26936621). In one family, this variant was identified with another pathogenic variant associated to cardiomyopathy in an affected parent but not the second pathogenic one identified in the proband (LMM data). This variant was also identified in two individuals from HCM families that underwent genetic testing but who did not yet present with clinical symptoms (Valente 2013 PMID: 23690394). Additionally, the p.Thr143An variant been reported by other clinical laboratories in ClinVar (Variation ID: 43382) has been also been identified in 0.005% (6/113252) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Mouse studies have shown that phosphorylation at threonine 143 (position 144 in mice) plays an important role in the regulation of muscle contractility (Noland 1995 PMID:7592712, Vahebi 2005 PMID: 15774859, Wang 2006 PMID: 17010989, Mathur 2008 PMID: 17872964). Computational and conversation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr143Asp variant is uncertain due to conflicting data. ACMG/AMP Criteria applied: PS3_Moderate. -

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy

Uncertain:2

Mar 07, 2024

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 asparagine, which is neutral and polar, at codon 143 of the TNNI3 protein (p.Thr143Asn). This variant is present in population databases (rs397516348, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of TNNI3-related conditions (PMID: 26936621, 27532257, 30731207, 34540771; Invitae). ClinVar contains an entry for this variant (Variation ID: 43382). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TNNI3 function (PMID: 15774859, 17010989, 17872964). 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. -

Jun 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with asparagine at codon 143 of the TNNI3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies have suggested that this variant may abolish the phosphorylation site and may therefore have deleterious impact on the protein function (PMID: 15774859, 17010989, 17872964). However, clinical significance of these observations is unclear. This variant has been reported in individuals affected with or referred for testing for hypertrophic cardiomyopathy (PMID: 23690394, 26936621, 27532257, 30731207). Three of these individuals also carried pathogenic variants in the MYBPC3 and TPM1 gene (PMID: 26936621). It has also been reported in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 34540771). This variant has been identified in 9/248930 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Left ventricular noncompaction cardiomyopathy

Pathogenic:1

Klaassen Lab, Charite University Medicine Berlin

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cardiomyopathy

Uncertain:1

Feb 20, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with asparagine at codon 143 of the TNNI3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. Experimental studies have suggested that this variant may abolish the phosphorylation site and may therefore have a deleterious impact on the protein function (PMID: 15774859, 17010989, 17872964). However, clinical significance of these observations is unclear. This variant has been reported in individuals affected with or suspected to be affected with hypertrophic cardiomyopathy (PMID: 23690394, 26936621, 27532257, 30731207, 32481709). Three of these individuals also carried pathogenic variants in the MYBPC3 and TPM1 gene (PMID: 26936621). It has also been reported in one individual affected with left ventricular noncompaction cardiomyopathy (PMID: 34540771). This variant has been identified in 9/248930 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Dec 18, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.428C>A (p.T143N) alteration is located in exon 7 (coding exon 7) of the TNNI3 gene. This alteration results from a C to A substitution at nucleotide position 428, causing the threonine (T) at amino acid position 143 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

CardioboostCm

Benign

0.098

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.57

D;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.060

MetaRNN

Benign

0.35

T;T

MetaSVM

Uncertain

-0.082

MutationAssessor

Benign

0.71

N;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.48

N;.

REVEL

Uncertain

0.45

Sift

Benign

0.39

T;.

Sift4G

Benign

0.32

T;T

Polyphen

0.0

B;.

Vest4

0.26

MutPred

0.41

Loss of phosphorylation at T143 (P = 0.0051);.;

MVP

0.85

MPC

0.76

ClinPred

0.11

GERP RS

4.7

Varity_R

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over