rs397516346

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_000363.5(TNNI3):c.39C>G(p.Arg13Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000637 in 1,602,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

TNNI3
NM_000363.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0260

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 links:

ENSG00000267110 (HGNC:):

ENSG00000267110 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 19-55157119-G-C is Benign according to our data. Variant chr19-55157119-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 43380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.026 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3	NM_000363.5 link	c.39C>G	p.Arg13Arg	synonymous_variant	Exon 3 of 8	ENST00000344887.10	NP_000354.4	P19429Q6FGX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNNI3	ENST00000344887.10 link	c.39C>G	p.Arg13Arg	synonymous_variant	Exon 3 of 8	1	NM_000363.5	ENSP00000341838.5	P19429
ENSG00000267110	ENST00000587871.1 link	n.*141C>G		non_coding_transcript_exon_variant	Exon 6 of 9	5		ENSP00000473050.1	M0R381
ENSG00000267110	ENST00000587871.1 link	n.*141C>G		3_prime_UTR_variant	Exon 6 of 9	5		ENSP00000473050.1	M0R381

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000223

AC:

AN:

224574

Hom.:

AF XY:

0.0000247

AC XY:

AN XY:

121468

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000487

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000655

AC:

AN:

1449934

Hom.:

Cov.:

AF XY:

0.0000569

AC XY:

AN XY:

719934

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000857

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Benign:2

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Aug 11, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg13Arg in exon 3 of TNNI3: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. -

Cardiomyopathy

Benign:1

Dec 31, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Apr 10, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 20, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.4

DANN

Benign

0.61

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over