rs3729837

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.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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.556

Publications

4 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=-0.72).

BP6

Variant 19-55157029-C-T is Benign according to our data. Variant chr19-55157029-C-T is described in ClinVar as Benign. ClinVar VariationId is 255944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
TNNI3	NM_000363.5 link	c.108+21G>A		intron_variant	Intron 3 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.108+21G>A		intron_variant	Intron 3 of 7	1	NM_000363.5	ENSP00000341838.5		P19429
ENSG00000267110	ENST00000587871.1 link	n.*210+21G>A		intron_variant	Intron 6 of 8	5		ENSP00000473050.1		M0R381

Frequencies

GnomAD3 genomes

AF:

0.0513

AC:

7796

AN:

151996

Hom.:

280

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0662

AC:

12169

AN:

183920

AF XY:

0.0711

show subpopulations

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 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.:

AF XY:

0.0699

AC XY:

49041

AN XY:

701526

show subpopulations

African (AFR)

AF:

0.0122

AC:

405

AN:

33190

American (AMR)

AF:

0.0375

AC:

1377

AN:

36714

Ashkenazi Jewish (ASJ)

AF:

0.0937

AC:

2373

AN:

25324

East Asian (EAS)

AF:

0.0251

AC:

969

AN:

38664

South Asian (SAS)

AF:

0.110

AC:

8869

AN:

80882

European-Finnish (FIN)

AF:

0.0628

AC:

2942

AN:

46836

Middle Eastern (MID)

AF:

0.155

AC:

708

AN:

4566

European-Non Finnish (NFE)

AF:

0.0681

AC:

74415

AN:

1093254

Other (OTH)

AF:

0.0748

AC:

4414

AN:

59020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

5541

11082

16623

22164

27705

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2790

5580

8370

11160

13950

<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:

0.0512

AC:

7788

AN:

152114

Hom.:

278

Cov.:

AF XY:

0.0516

AC XY:

3834

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0123

AC:

509

AN:

41506

American (AMR)

AF:

0.0411

AC:

629

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0968

AC:

336

AN:

3470

East Asian (EAS)

AF:

0.0422

AC:

218

AN:

5170

South Asian (SAS)

AF:

0.104

AC:

502

AN:

4818

European-Finnish (FIN)

AF:

0.0595

AC:

632

AN:

10616

Middle Eastern (MID)

AF:

0.146

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0688

AC:

4673

AN:

67934

Other (OTH)

AF:

0.0697

AC:

147

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

383

766

1150

1533

1916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<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:

0.0654

Hom.:

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

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.72

CADD

Benign

5.7

(source)

DANN

Benign

0.94

PhyloP100

-0.56

PromoterAI

0.037

Neutral

(source)

Mutation Taster

=11/89

disease causing

(source)

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

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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