rs77615401

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000363.5(TNNI3):c.244C>T(p.Pro82Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,612,562 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P82R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0064 ( 17 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 12 hom. )

Consequence

TNNI3
NM_000363.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:29O:1

Conservation

PhyloP100: 5.66

Publications

27 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 (MetaRNN=0.009637028).

BP6

Variant 19-55156239-G-A is Benign according to our data. Variant chr19-55156239-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 12421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00638 (972/152278) while in subpopulation AFR AF = 0.0224 (932/41542). AF 95% confidence interval is 0.0212. There are 17 homozygotes in GnomAd4. There are 476 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3	NM_000363.5 link	c.244C>T	p.Pro82Ser	missense_variant	Exon 5 of 8	ENST00000344887.10	NP_000354.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TNNI3	ENST00000344887.10 link	c.244C>T	p.Pro82Ser	missense_variant	Exon 5 of 8	1	NM_000363.5	ENSP00000341838.5
ENSG00000267110	ENST00000587871.1 link	n.*346C>T		non_coding_transcript_exon_variant	Exon 8 of 9	5		ENSP00000473050.1
ENSG00000267110	ENST00000587871.1 link	n.*346C>T		3_prime_UTR_variant	Exon 8 of 9	5		ENSP00000473050.1

Frequencies

GnomAD3 genomes

AF:

0.00637

AC:

970

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0225

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00145

AC:

350

AN:

241630

AF XY:

0.00123

show subpopulations

Gnomad AFR exome

AF:

0.0230

Gnomad AMR exome

AF:

0.000438

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000102

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.000616

AC:

899

AN:

1460284

Hom.:

Cov.:

AF XY:

0.000563

AC XY:

409

AN XY:

726512

show subpopulations

African (AFR)

AF:

0.0226

AC:

755

AN:

33474

American (AMR)

AF:

0.000582

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52216

Middle Eastern (MID)

AF:

0.000869

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1111818

Other (OTH)

AF:

0.00124

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00638

AC:

972

AN:

152278

Hom.:

Cov.:

AF XY:

0.00639

AC XY:

476

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0224

AC:

932

AN:

41542

American (AMR)

AF:

0.00144

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68010

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

148

197

246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00202

Hom.:

Bravo

AF:

0.00694

ESP6500AA

AF:

0.0203

AC:

ESP6500EA

AF:

0.000132

AC:

ExAC

AF:

0.00164

AC:

195

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:29Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Aug 09, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant Summary: The c.244C>T variant involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.17%, predominantly observed in the African subpopulation at a frequency of 2.3% including 3 homozygous occurrences. This frequency exceeds the maximal expected allele frequency for a pathogenic variant in TNNI3 (0.0125%), suggesting this is a benign polymorphism found primarily in population(s) of African origin. The variant has been reported in the literature in HCM patients and controls, mostly of African descent. However, mouse model studies have suggested the variant to be a disease-modifying factor for dysfunction and adverse remodeling with aging and chronic pressure overload (Ramirez-Correa_2015), although the relationship of this finding to a monogenic causation is unclear, therefore the evidence is not weighed in its classification. Multiple reputable clinical labs have classified the variant as benign. Taken together, this variant is classified as Benign. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TNNI3: BS1, BS2 -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 11, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23299917, 22995991, 25324519, 20981092, 18175163, 23967088, 11815426, 27150586, 21310275, 27532831, 26332594, 31006259) -

Jan 31, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:7

Feb 09, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pro82Ser in exon 5 of TNNI3: This variant is classified as benign based on its h igh frequency in the general population (dbSNP rs77615401; NHLBI Exome Sequencin g Project, http://evs.gs.washington.edu/EVS). A=57/G=2853 -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 26, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:3

Mar 07, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 19, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy 7

Benign:1Other:1

Apr 05, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jul 01, 2008

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated Cardiomyopathy, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy;C2751492:Amyloidosis, hereditary systemic 1

Benign:1

Jun 03, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 2A

Benign:1

Apr 05, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiomyopathy, familial restrictive, 1

Benign:1

Apr 05, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hypertrophic cardiomyopathy 7;C1861861:Cardiomyopathy, familial restrictive, 1;C2678474:Dilated cardiomyopathy 2A;C2750091:Dilated cardiomyopathy 1FF

Benign:1

Apr 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial restrictive cardiomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 25, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.0096

T;T

MetaSVM

Uncertain

0.62

MutationAssessor

Benign

1.7

L;.

PhyloP100

5.7

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.4

D;.

REVEL

Pathogenic

0.76

Sift

Benign

0.077

T;.

Sift4G

Benign

0.10

T;T

Polyphen

1.0

D;.

Vest4

0.28

MVP

0.96

MPC

1.0

ClinPred

0.045

GERP RS

4.4

PromoterAI

0.024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.63

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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