chr19-55154766-G-C

Variant names:

• chr19-55154766-G-C
• rs777177571
• NM_000363.5:c.347C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000363.5(TNNI3):​c.347C>G​(p.Ala116Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A116V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 0.929
• Publications: 6 publications found

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
• hypertrophic cardiomyopathy 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: AR, AD Classification: STRONG 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

ENSG00000267110 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000363.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3	NM_000363.5	MANE Select	c.347C>G	p.Ala116Gly	missense	Exon 6 of 8	NP_000354.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3	ENST00000344887.10	TSL:1 MANE Select	c.347C>G	p.Ala116Gly	missense	Exon 6 of 8	ENSP00000341838.5	P19429
	ENSG00000267110	ENST00000587871.1	TSL:5	n.*449C>G		non_coding_transcript_exon	Exon 9 of 9	ENSP00000473050.1	M0R381
	ENSG00000267110	ENST00000587871.1	TSL:5	n.*449C>G		3_prime_UTR	Exon 9 of 9	ENSP00000473050.1	M0R381

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152230 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249430 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111978

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152230 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Cardiomyopathy (2)
-	2	-	Hypertrophic cardiomyopathy (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Hypertrophic cardiomyopathy 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
CardioboostCm	Benign	0.0043
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.93
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.37
Sift	Benign	0.20	T
Sift4G	Benign	0.30	T
Polyphen		0.17	B
Vest4		0.82
MVP		0.91
MPC		0.67
ClinPred		0.51	D
GERP RS		3.4
Varity_R		0.47
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs777177571; hg19: chr19-55666134;