rs1555864037

Positions:

• chr19-55156278-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000363.5(TNNI3):​c.205C>A​(p.Arg69Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R69R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Troponin I, cardiac muscle (size 208) in uniprot entity TNNI3_HUMAN there are 86 pathogenic changes around while only 10 benign (90%) in NM_000363.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17867565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI3	NM_000363.5	c.205C>A	p.Arg69Ser	missense_variant	5/8	ENST00000344887.10	NP_000354.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10	c.205C>A	p.Arg69Ser	missense_variant	5/8	1	NM_000363.5	ENSP00000341838	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458708 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725612

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

This variant is not present in population databases (gnomAD no frequency). 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. An algorithm developed specifically for the TNNI3 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). ClinVar contains an entry for this variant (Variation ID: 454403). This variant has not been reported in the literature in individuals affected with TNNI3-related conditions. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 69 of the TNNI3 protein (p.Arg69Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
CardioboostCm	Benign	0.0039
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.33	N;.
REVEL	Uncertain	0.33
Sift	Benign	0.30	T;.
Sift4G	Benign	0.57	T;T
Polyphen		0.0020	B;.
Vest4		0.17
MutPred		0.36		Gain of phosphorylation at R69 (P = 0.0033);.;
MVP		0.91
MPC		0.75
ClinPred		0.42	T
GERP RS		3.3
Varity_R		0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555864037; hg19: chr19-55667646; COSMIC: COSV104420835; COSMIC: COSV104420835;