rs1555864366
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_000363.5(TNNI3):c.79C>T(p.Arg27Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R27P) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TNNI3
NM_000363.5 missense
NM_000363.5 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 1.44
Publications
1 publications found
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 Gene-Disease associations (from GenCC):
- hypertrophic cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- hypertrophic cardiomyopathy 7Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- dilated cardiomyopathy 2AInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- cardiomyopathy, familial restrictive, 1Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- dilated cardiomyopathy 1FFInheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- dilated cardiomyopathyInheritance: AR, AD Classification: STRONG Submitted by: ClinGen
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial isolated restrictive cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000363.5. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TNNI3 | TSL:1 MANE Select | c.79C>T | p.Arg27Cys | missense | Exon 3 of 8 | ENSP00000341838.5 | P19429 | ||
| ENSG00000267110 | TSL:5 | n.*181C>T | non_coding_transcript_exon | Exon 6 of 9 | ENSP00000473050.1 | M0R381 | |||
| ENSG00000267110 | TSL:5 | n.*181C>T | 3_prime_UTR | Exon 6 of 9 | ENSP00000473050.1 | M0R381 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1449060Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 719358
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1449060
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
719358
African (AFR)
AF:
AC:
0
AN:
33422
American (AMR)
AF:
AC:
0
AN:
41894
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25702
East Asian (EAS)
AF:
AC:
0
AN:
39282
South Asian (SAS)
AF:
AC:
0
AN:
83290
European-Finnish (FIN)
AF:
AC:
0
AN:
52240
Middle Eastern (MID)
AF:
AC:
0
AN:
5264
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1107988
Other (OTH)
AF:
AC:
0
AN:
59978
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions
View on ClinVar Significance:Uncertain significance
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
-
1
-
Cardiovascular phenotype (1)
1
-
-
Dilated cardiomyopathy 1A (1)
-
1
-
Hypertrophic cardiomyopathy (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
PhyloP100
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Benign
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of methylation at R27 (P = 0.0242)
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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