rs3729836

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000363.5(TNNI3):​c.25-8T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,595,860 control chromosomes in the GnomAD database, including 61,446 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 11970 hom., cov: 31)
Exomes 𝑓: 0.24 ( 49476 hom. )

Consequence

TNNI3
NM_000363.5 splice_region, intron

Scores

2
Splicing: ADA: 0.002082
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24

Conservation

PhyloP100: -1.35
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.93).
BP6
Variant 19-55157141-A-T is Benign according to our data. Variant chr19-55157141-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 43371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55157141-A-T is described in Lovd as [Benign]. Variant chr19-55157141-A-T is described in Lovd as [Likely_benign]. Variant chr19-55157141-A-T is described in Lovd as [Likely_pathogenic].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TNNI3NM_000363.5 linkc.25-8T>A splice_region_variant, intron_variant Intron 2 of 7 ENST00000344887.10 NP_000354.4 P19429Q6FGX2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNNI3ENST00000344887.10 linkc.25-8T>A splice_region_variant, intron_variant Intron 2 of 7 1 NM_000363.5 ENSP00000341838.5 P19429
ENSG00000267110ENST00000587871.1 linkn.*132-13T>A intron_variant Intron 5 of 8 5 ENSP00000473050.1 M0R381

Frequencies

GnomAD3 genomes
AF:
0.353
AC:
53463
AN:
151578
Hom.:
11930
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.612
Gnomad AMI
AF:
0.145
Gnomad AMR
AF:
0.399
Gnomad ASJ
AF:
0.214
Gnomad EAS
AF:
0.440
Gnomad SAS
AF:
0.441
Gnomad FIN
AF:
0.227
Gnomad MID
AF:
0.316
Gnomad NFE
AF:
0.201
Gnomad OTH
AF:
0.353
GnomAD3 exomes
AF:
0.316
AC:
68587
AN:
216832
Hom.:
13019
AF XY:
0.309
AC XY:
36195
AN XY:
117204
show subpopulations
Gnomad AFR exome
AF:
0.624
Gnomad AMR exome
AF:
0.487
Gnomad ASJ exome
AF:
0.212
Gnomad EAS exome
AF:
0.425
Gnomad SAS exome
AF:
0.422
Gnomad FIN exome
AF:
0.225
Gnomad NFE exome
AF:
0.205
Gnomad OTH exome
AF:
0.308
GnomAD4 exome
AF:
0.242
AC:
348815
AN:
1444164
Hom.:
49476
Cov.:
35
AF XY:
0.245
AC XY:
175355
AN XY:
716598
show subpopulations
Gnomad4 AFR exome
AF:
0.631
Gnomad4 AMR exome
AF:
0.481
Gnomad4 ASJ exome
AF:
0.214
Gnomad4 EAS exome
AF:
0.421
Gnomad4 SAS exome
AF:
0.413
Gnomad4 FIN exome
AF:
0.231
Gnomad4 NFE exome
AF:
0.200
Gnomad4 OTH exome
AF:
0.279
GnomAD4 genome
AF:
0.353
AC:
53569
AN:
151696
Hom.:
11970
Cov.:
31
AF XY:
0.355
AC XY:
26325
AN XY:
74090
show subpopulations
Gnomad4 AFR
AF:
0.612
Gnomad4 AMR
AF:
0.400
Gnomad4 ASJ
AF:
0.214
Gnomad4 EAS
AF:
0.440
Gnomad4 SAS
AF:
0.441
Gnomad4 FIN
AF:
0.227
Gnomad4 NFE
AF:
0.201
Gnomad4 OTH
AF:
0.360
Alfa
AF:
0.243
Hom.:
1792
Bravo
AF:
0.378
Asia WGS
AF:
0.520
AC:
1806
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:24
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:9
Oct 28, 2006
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 20, 2020
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 28, 2012
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 15, 2013
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. c.25-8T>A. At the time of testing, the testing lab classified this as a variant of unknown significance. However, a review of dbSNP reveals that this variant is common in general populations samples (rs3729836). It is frequently seen in NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 7/15/13). It is reported in 3,907/12,358 alleles (as of 7/15/13) -

Cardiomyopathy, familial restrictive, 1 Benign:2
Sep 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiomyopathy Benign:2
Mar 09, 2018
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 10, 2022
Cohesion Phenomics
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 7 Benign:2
Sep 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hypertrophic cardiomyopathy Benign:2
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dilated cardiomyopathy 2A Benign:2
Sep 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary ciliary dyskinesia Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dilated Cardiomyopathy, Recessive Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Familial restrictive cardiomyopathy Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.93
CADD
Benign
4.1
DANN
Benign
0.67
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0021
dbscSNV1_RF
Benign
0.14
SpliceAI score (max)
0.16
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: rs3729836; hg19: chr19-55668509; COSMIC: COSV61277049; COSMIC: COSV61277049; API