19-55156590-C-T

Variant names:

• chr19-55156590-C-T
• rs73617692
• NM_000363.5:c.150+13G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000363.5(TNNI3):​c.150+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,560,062 control chromosomes in the GnomAD database, including 2,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (1127 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (1014 hom.)
• Consequence: TNNI3 NM_000363.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.0510
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• cardiomyopathy, familial restrictive, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1FF

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AR, AD Classification: STRONG Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000267110 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-55156590-C-T is Benign according to our data. Variant chr19-55156590-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000363.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3	NM_000363.5	MANE Select	c.150+13G>A		intron	N/A	NP_000354.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3	ENST00000344887.10	TSL:1 MANE Select	c.150+13G>A		intron	N/A	ENSP00000341838.5	P19429
	ENSG00000267110	ENST00000587871.1	TSL:5	n.*252+13G>A		intron	N/A	ENSP00000473050.1	M0R381
	TNNI3	ENST00000665070.1		c.150+13G>A		intron	N/A	ENSP00000499482.1	A0A590UJN1

Frequencies

GnomAD3 genomes AF: 0.0682 AC: 10376 AN: 152084 Hom.: 1120 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0307

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.0522

GnomAD2 exomes AF: 0.0181 AC: 3057 AN: 169018 AF XY: 0.0146

Gnomad AFR exome AF: 0.236

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.00672

Gnomad EAS exome AF: 0.00355

Gnomad FIN exome AF: 0.000314

Gnomad NFE exome AF: 0.00287

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.00887 AC: 12493 AN: 1407860 Hom.: 1014 Cov.: 33 AF XY: 0.00795 AC XY: 5527 AN XY: 695280

African (AFR) AF: 0.239 AC: 7669 AN: 32046

American (AMR) AF: 0.0175 AC: 650 AN: 37062

Ashkenazi Jewish (ASJ) AF: 0.00676 AC: 172 AN: 25436

East Asian (EAS) AF: 0.00161 AC: 59 AN: 36722

South Asian (SAS) AF: 0.00436 AC: 349 AN: 80116

European-Finnish (FIN) AF: 0.000543 AC: 27 AN: 49762

Middle Eastern (MID) AF: 0.0250 AC: 142 AN: 5682

European-Non Finnish (NFE) AF: 0.00203 AC: 2193 AN: 1082678

Other (OTH) AF: 0.0211 AC: 1232 AN: 58356

GnomAD4 genome AF: 0.0684 AC: 10415 AN: 152202 Hom.: 1127 Cov.: 32 AF XY: 0.0659 AC XY: 4902 AN XY: 74410

African (AFR) AF: 0.230 AC: 9531 AN: 41468

American (AMR) AF: 0.0306 AC: 468 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00483 AC: 25 AN: 5178

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4830

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10618

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 68032

Other (OTH) AF: 0.0554 AC: 117 AN: 2112

Alfa AF: 0.0312 Hom.: 155

Bravo AF: 0.0790

Asia WGS AF: 0.0550 AC: 192 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Hypertrophic cardiomyopathy (3)
-	-	2	not provided (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiomyopathy, familial restrictive, 1 (1)
-	-	1	Dilated cardiomyopathy 2A (1)
-	-	1	Dilated Cardiomyopathy, Recessive (1)
-	-	1	Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome (1)
-	-	1	Familial restrictive cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 7 (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.3
DANN	Benign	0.63
PhyloP100		-0.051
PromoterAI		-0.0090	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs73617692; hg19: chr19-55667958;