rs3729836

Positions:

• chr19-55157141-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000363.5(TNNI3):​c.25-8T>A variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002082
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: -1.35

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 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/exons	MANE	UniProt
TNNI3	NM_000363.5	c.25-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000344887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI3	ENST00000344887.10	c.25-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000363.5	P1

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53463 AN: 151578 Hom.: 11930 Cov.: 31

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

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

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

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

Submissions by phenotype

not specified Benign:9

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 28, 2006	- -
Benign, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 15, 2013	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) -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 20, 2020	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2012	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. -

Cardiomyopathy, familial restrictive, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

Hypertrophic cardiomyopathy 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Dilated cardiomyopathy 2A Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Hypertrophic cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Familial restrictive cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Other links and lift over

dbSNP: rs3729836; hg19: chr19-55668509; COSMIC: COSV61277049; COSMIC: COSV61277049;