rs3729710

chr19-55156285-C-Achr19-55156285-C-Gchr19-55156285-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000363.5(TNNI3):c.198G>T(p.Glu66Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,760 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E66G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0960

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 4 ACMG points.

• PM1: In a chain Troponin I, cardiac muscle (size 208) in uniprot entity TNNI3_HUMAN there are 152 pathogenic changes around while only 19 benign (89%) in NM_000363.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNI3	NM_000363.5	c.198G>T	p.Glu66Asp	missense_variant	5/8	ENST00000344887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI3	ENST00000344887.10	c.198G>T	p.Glu66Asp	missense_variant	5/8	1	NM_000363.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458760 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725636

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
CardioboostCm	Benign	0.0039
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;D
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.63	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.0082	P;P
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.6	N;.
REVEL	Uncertain	0.35
Sift	Benign	0.17	T;.
Sift4G	Benign	0.20	T;T
Polyphen		0.0	B;.
Vest4		0.13
MutPred		0.43		Loss of MoRF binding (P = 0.3383);.;
MVP		0.90
MPC		0.60
ClinPred		0.62	D
GERP RS		-0.88
Varity_R		0.39

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: rs3729710; hg19: chr19-55667653;