rs3729837

Positions:

• chr19-55157029-C-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.108+21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0664 in 1,570,564 control chromosomes in the GnomAD database, including 4,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (278 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3722 hom.)
• Consequence: TNNI3 NM_000363.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.556

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=-0.72).
• BP6: Variant 19-55157029-C-T is Benign according to our data. Variant chr19-55157029-C-T is described in ClinVar as [Benign]. Clinvar id is 255944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55157029-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI3	NM_000363.5	c.108+21G>A		intron_variant		ENST00000344887.10	NP_000354.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10	c.108+21G>A		intron_variant		1	NM_000363.5	ENSP00000341838	P1

Frequencies

GnomAD3 genomes AF: 0.0513 AC: 7796 AN: 151996 Hom.: 280 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0413

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.0425

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0595

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0688

Gnomad OTH AF: 0.0699

GnomAD3 exomes AF: 0.0662 AC: 12169 AN: 183920 Hom.: 543 AF XY: 0.0711 AC XY: 7005 AN XY: 98500

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.0379

Gnomad ASJ exome AF: 0.0958

Gnomad EAS exome AF: 0.0449

Gnomad SAS exome AF: 0.108

Gnomad FIN exome AF: 0.0571

Gnomad NFE exome AF: 0.0706

Gnomad OTH exome AF: 0.0869

GnomAD4 exome AF: 0.0680 AC: 96472 AN: 1418450 Hom.: 3722 Cov.: 33 AF XY: 0.0699 AC XY: 49041 AN XY: 701526

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.0375

Gnomad4 ASJ exome AF: 0.0937

Gnomad4 EAS exome AF: 0.0251

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.0628

Gnomad4 NFE exome AF: 0.0681

Gnomad4 OTH exome AF: 0.0748

GnomAD4 genome AF: 0.0512 AC: 7788 AN: 152114 Hom.: 278 Cov.: 32 AF XY: 0.0516 AC XY: 3834 AN XY: 74374

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.0411

Gnomad4 ASJ AF: 0.0968

Gnomad4 EAS AF: 0.0422

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0595

Gnomad4 NFE AF: 0.0688

Gnomad4 OTH AF: 0.0697

Alfa AF: 0.0654 Hom.: 75

Bravo AF: 0.0460

Asia WGS AF: 0.0620 AC: 216 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.7
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3729837; hg19: chr19-55668397;