NM_000363.5:c.12-129A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000363.5(TNNI3):c.12-129A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,580,076 control chromosomes in the GnomAD database, including 64,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 13194 hom., cov: 32)

Exomes 𝑓: 0.24 ( 50936 hom. )

Consequence

TNNI3
NM_000363.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.130

Publications

13 publications found

Variant links:

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
dilated cardiomyopathy 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
hypertrophic cardiomyopathy 7
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
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: AD Classification: MODERATE 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

TNNI3 links:

ENSG00000267110 (HGNC:):

ENSG00000267110 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 19-55157437-T-C is Benign according to our data. Variant chr19-55157437-T-C is described in ClinVar as Benign. ClinVar VariationId is 1264197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3	NM_000363.5 link	c.12-129A>G		intron_variant	Intron 1 of 7	ENST00000344887.10	NP_000354.4	P19429Q6FGX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10 link	c.12-129A>G		intron_variant	Intron 1 of 7	1	NM_000363.5	ENSP00000341838.5		P19429
ENSG00000267110	ENST00000587871.1 link	n.*131+125A>G		intron_variant	Intron 5 of 8	5		ENSP00000473050.1		M0R381

Frequencies

GnomAD3 genomes

AF:

0.365

AC:

55478

AN:

151830

Hom.:

13154

Cov.:

show subpopulations

Gnomad AFR

AF:

0.657

Gnomad AMI

AF:

0.147

Gnomad AMR

AF:

0.404

Gnomad ASJ

AF:

0.214

Gnomad EAS

AF:

0.441

Gnomad SAS

AF:

0.441

Gnomad FIN

AF:

0.226

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.201

Gnomad OTH

AF:

0.360

GnomAD4 exome

AF:

0.245

AC:

349428

AN:

1428128

Hom.:

50936

Cov.:

AF XY:

0.248

AC XY:

175709

AN XY:

709880

show subpopulations

African (AFR)

AF:

0.677

AC:

22182

AN:

32784

American (AMR)

AF:

0.490

AC:

21374

AN:

43660

Ashkenazi Jewish (ASJ)

AF:

0.213

AC:

5329

AN:

24980

East Asian (EAS)

AF:

0.421

AC:

16567

AN:

39370

South Asian (SAS)

AF:

0.414

AC:

35031

AN:

84622

European-Finnish (FIN)

AF:

0.231

AC:

12129

AN:

52494

Middle Eastern (MID)

AF:

0.334

AC:

1885

AN:

5648

European-Non Finnish (NFE)

AF:

0.201

AC:

218314

AN:

1085554

Other (OTH)

AF:

0.282

AC:

16617

AN:

59016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

13598

27195

40793

54390

67988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8088

16176

24264

32352

40440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.366

AC:

55586

AN:

151948

Hom.:

13194

Cov.:

AF XY:

0.367

AC XY:

27288

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.658

AC:

27214

AN:

41388

American (AMR)

AF:

0.404

AC:

6173

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.214

AC:

744

AN:

3472

East Asian (EAS)

AF:

0.441

AC:

2273

AN:

5156

South Asian (SAS)

AF:

0.440

AC:

2120

AN:

4816

European-Finnish (FIN)

AF:

0.226

AC:

2398

AN:

10588

Middle Eastern (MID)

AF:

0.306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.201

AC:

13668

AN:

67946

Other (OTH)

AF:

0.367

AC:

772

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1504

3008

4512

6016

7520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

498

996

1494

1992

2490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.303

Hom.:

5402

Bravo

AF:

0.392

Asia WGS

AF:

0.521

AC:

1809

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

8.8

(source)

DANN

Benign

0.57

PhyloP100

0.13

PromoterAI

-0.024

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over