rs3729836

Variant names:

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

Splicing: ADA: 0.002082

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]

TNNI3 links:

ENSG00000267110 (HGNC:):

ENSG00000267110 links:

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
TNNI3	NM_000363.5 link	c.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
TNNI3	ENST00000344887.10 link	c.25-8T>A		splice_region_variant, intron_variant	Intron 2 of 7	1	NM_000363.5	ENSP00000341838.5		P19429
ENSG00000267110	ENST00000587871.1 link	n.*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.:

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.:

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.:

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, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 10, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

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

Hypertrophic cardiomyopathy

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely 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

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

- -

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

- -

Primary ciliary dyskinesia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: 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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over