rs77615401

chr19-55156239-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27 O:1
• Conservation: PhyloP100: 5.66

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a chain Troponin I, cardiac muscle (size 208) in uniprot entity TNNI3_HUMAN there are 152 pathogenic changes around while only 19 benign (89%) in NM_000363.5
• 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 [Likely_benign]. Clinvar id is 12421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55156239-G-A is described in Lovd as [Benign]. Variant chr19-55156239-G-A is described in Lovd as [Likely_benign]. Variant chr19-55156239-G-A is described in Lovd as [Pathogenic].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNI3	NM_000363.5	c.244C>T	p.Pro82Ser	missense_variant	5/8	ENST00000344887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI3	ENST00000344887.10	c.244C>T	p.Pro82Ser	missense_variant	5/8	1	NM_000363.5	P1

Frequencies

GnomAD3 genomes AF: 0.00637 AC: 970 AN: 152162 Hom.: 17 Cov.: 32

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

GnomAD3 exomes AF: 0.00145 AC: 350 AN: 241630 Hom.: 4 AF XY: 0.00123 AC XY: 164 AN XY: 132910

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 SAS exome AF: 0.0000329

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.: 12 Cov.: 32 AF XY: 0.000563 AC XY: 409 AN XY: 726512

Gnomad4 AFR exome AF: 0.0226

Gnomad4 AMR exome AF: 0.000582

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00638 AC: 972 AN: 152278 Hom.: 17 Cov.: 32 AF XY: 0.00639 AC XY: 476 AN XY: 74458

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00359 Hom.: 1

Bravo AF: 0.00694

ESP6500AA AF: 0.0203 AC: 70

ESP6500EA AF: 0.000132 AC: 1

ExAC AF: 0.00164 AC: 195

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:27 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2016	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. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 31, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2018	This variant is associated with the following publications: (PMID: 23299917, 22995991, 25324519, 20981092, 18175163, 23967088, 11815426, 27150586, 21310275, 27532831, 26332594, 31006259) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 26, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 09, 2012	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 -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cardiomyopathy Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 19, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 07, 2019	- -

Hypertrophic cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hypertrophic cardiomyopathy 7 Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 05, 2018	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. -
risk factor, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -

Cardiomyopathy, familial restrictive, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 05, 2018

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. -

Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiomyopathy;C2751492:Familial amyloid neuropathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 03, 2019

- -

Dilated Cardiomyopathy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 18, 2022

- -

Dilated cardiomyopathy 2A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 05, 2018

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. -

Familial restrictive cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2015

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	T
BayesDel_noAF	Uncertain	0.030
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0096	T;T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.76	T
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	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.63

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

LitVar

Other links and lift over

dbSNP: rs77615401; hg19: chr19-55667607; COSMIC: COSV61276775; COSMIC: COSV61276775;