19-55151917-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5

The NM_000363.5(TNNI3):​c.550G>A​(p.Glu184Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E184Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TNNI3
NM_000363.5 missense, splice_region

Scores

1
10
9
Splicing: ADA: 0.9519
1
1

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.03
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000363.5
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-55151917-C-T is Pathogenic according to our data. Variant chr19-55151917-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43394.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-55151917-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TNNI3NM_000363.5 linkc.550G>A p.Glu184Lys missense_variant, splice_region_variant Exon 8 of 8 ENST00000344887.10 NP_000354.4 P19429Q6FGX2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNNI3ENST00000344887.10 linkc.550G>A p.Glu184Lys missense_variant, splice_region_variant Exon 8 of 8 1 NM_000363.5 ENSP00000341838.5 P19429

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1
Sep 06, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.53
CardioboostCm
Uncertain
0.88
BayesDel_addAF
Uncertain
0.069
T
BayesDel_noAF
Benign
-0.14
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.70
D;T
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.12
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Pathogenic
0.30
D
MetaRNN
Uncertain
0.52
D;D
MetaSVM
Uncertain
0.16
D
MutationAssessor
Benign
1.4
L;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-2.3
N;.
REVEL
Benign
0.26
Sift
Benign
0.18
T;.
Sift4G
Benign
0.12
T;T
Polyphen
0.0010
B;.
Vest4
0.24
MutPred
0.26
Gain of MoRF binding (P = 0.0019);.;
MVP
0.85
MPC
0.88
ClinPred
0.85
D
GERP RS
4.5
Varity_R
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.95
dbscSNV1_RF
Pathogenic
0.73
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs397516356; hg19: chr19-55663285; API