rs11667847

Positions:

• chr19-55157451-A-G

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.11+128T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,573,404 control chromosomes in the GnomAD database, including 29,067 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4011 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25056 hom.)
• Consequence: TNNI3 NM_000363.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.90

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]

ENSG00000267110 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-55157451-A-G is Benign according to our data. Variant chr19-55157451-A-G is described in ClinVar as [Benign]. Clinvar id is 1290282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55157451-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI3	NM_000363.5	c.11+128T>C		intron_variant		ENST00000344887.10	NP_000354.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10	c.11+128T>C		intron_variant		1	NM_000363.5	ENSP00000341838.5
ENSG00000267110	ENST00000587871.1	n.*131+111T>C		intron_variant		5		ENSP00000473050.1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33254 AN: 151756 Hom.: 4005 Cov.: 32

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.223

GnomAD4 exome AF: 0.183 AC: 259569 AN: 1421530 Hom.: 25056 Cov.: 26 AF XY: 0.186 AC XY: 131245 AN XY: 706214

Gnomad4 AFR exome AF: 0.335

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.172

Gnomad4 EAS exome AF: 0.178

Gnomad4 SAS exome AF: 0.275

Gnomad4 FIN exome AF: 0.198

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.198

GnomAD4 genome AF: 0.219 AC: 33288 AN: 151874 Hom.: 4011 Cov.: 32 AF XY: 0.219 AC XY: 16243 AN XY: 74252

Gnomad4 AFR AF: 0.325

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.173

Gnomad4 EAS AF: 0.213

Gnomad4 SAS AF: 0.280

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.225

Alfa AF: 0.192 Hom.: 370

Bravo AF: 0.219

Asia WGS AF: 0.264 AC: 916 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs11667847; hg19: chr19-55668819; COSMIC: COSV61276040; COSMIC: COSV61276040;