19-55154042-C-T

Variant names:

• chr19-55154042-C-T
• rs3729841
• NM_000363.5:c.537G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_000363.5(TNNI3):​c.537G>A​(p.Glu179Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,611,958 control chromosomes in the GnomAD database, including 4,094 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene TNNI3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.051 (275 hom., cov: 30)
  • Exomes 𝑓: 0.068 (3819 hom.)
• Consequence: TNNI3 NM_000363.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:18
• Conservation: PhyloP100: -0.293
• Publications: 20 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

ACMG classification

Specifications for TNNI3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 19-55154042-C-T is Benign according to our data. Variant chr19-55154042-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43391.
• BP7: Synonymous conserved (PhyloP=-0.293 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0949 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.537G>A	p.Glu179Glu	synonymous	Exon 7 of 8	NP_000354.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3	ENST00000344887.10	TSL:1 MANE Select	c.537G>A	p.Glu179Glu	synonymous	Exon 7 of 8	ENSP00000341838.5	P19429
	TNNI3	ENST00000665070.1		c.570G>A	p.Glu190Glu	synonymous	Exon 7 of 8	ENSP00000499482.1	A0A590UJN1
	TNNI3	ENST00000714238.1		c.525G>A	p.Glu175Glu	synonymous	Exon 7 of 8	ENSP00000519518.1	A0AAQ5BHR0

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7759 AN: 151904 Hom.: 277 Cov.: 30

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0410

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.0420

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0598

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0686

Gnomad OTH AF: 0.0699

GnomAD2 exomes AF: 0.0651 AC: 16183 AN: 248552 AF XY: 0.0701

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.0360

Gnomad ASJ exome AF: 0.0952

Gnomad EAS exome AF: 0.0464

Gnomad FIN exome AF: 0.0576

Gnomad NFE exome AF: 0.0708

Gnomad OTH exome AF: 0.0855

GnomAD4 exome AF: 0.0678 AC: 99045 AN: 1459936 Hom.: 3819 Cov.: 32 AF XY: 0.0699 AC XY: 50744 AN XY: 726288

African (AFR) AF: 0.0123 AC: 410 AN: 33440

American (AMR) AF: 0.0360 AC: 1612 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0934 AC: 2442 AN: 26134

East Asian (EAS) AF: 0.0259 AC: 1030 AN: 39698

South Asian (SAS) AF: 0.109 AC: 9387 AN: 86206

European-Finnish (FIN) AF: 0.0627 AC: 3299 AN: 52582

Middle Eastern (MID) AF: 0.160 AC: 786 AN: 4904

European-Non Finnish (NFE) AF: 0.0680 AC: 75592 AN: 1111978

Other (OTH) AF: 0.0744 AC: 4487 AN: 60272

GnomAD4 genome AF: 0.0510 AC: 7751 AN: 152022 Hom.: 275 Cov.: 30 AF XY: 0.0512 AC XY: 3807 AN XY: 74296

African (AFR) AF: 0.0122 AC: 505 AN: 41484

American (AMR) AF: 0.0409 AC: 624 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0968 AC: 336 AN: 3470

East Asian (EAS) AF: 0.0417 AC: 215 AN: 5150

South Asian (SAS) AF: 0.102 AC: 489 AN: 4778

European-Finnish (FIN) AF: 0.0598 AC: 633 AN: 10594

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.0686 AC: 4660 AN: 67954

Other (OTH) AF: 0.0696 AC: 147 AN: 2112

Alfa AF: 0.0649 Hom.: 769

Bravo AF: 0.0458

Asia WGS AF: 0.0620 AC: 216 AN: 3478

EpiCase AF: 0.0742

EpiControl AF: 0.0768

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Cardiomyopathy (2)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	2	Hypertrophic cardiomyopathy 7 (2)
-	-	1	Cardiomyopathy, familial restrictive, 1 (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 2A (1)
-	-	1	Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	6.4
DANN	Benign	0.81
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3729841; hg19: chr19-55665410;