NM_000363.5:c.204G>T

Variant names:

• chr19-55156279-C-A
• rs3729711
• NM_000363.5:c.204G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000363.5(TNNI3):​c.204G>T​(p.Arg68Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.049 in 1,611,002 control chromosomes in the GnomAD database, including 2,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R68R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.039 (165 hom., cov: 32)
  • Exomes 𝑓: 0.050 (1954 hom.)
• Consequence: TNNI3 NM_000363.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:19
• Conservation: PhyloP100: 0.100
• Publications: 13 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021397173).
• BP6: Variant 19-55156279-C-A is Benign according to our data. Variant chr19-55156279-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43366.
• BP7: Synonymous conserved (PhyloP=0.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

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.204G>T	p.Arg68Arg	synonymous	Exon 5 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.204G>T	p.Arg68Arg	synonymous	Exon 5 of 8	ENSP00000341838.5	P19429
	ENSG00000267110	ENST00000587871.1	TSL:5	n.*306G>T		non_coding_transcript_exon	Exon 8 of 9	ENSP00000473050.1	M0R381
	ENSG00000267110	ENST00000587871.1	TSL:5	n.*306G>T		3_prime_UTR	Exon 8 of 9	ENSP00000473050.1	M0R381

Frequencies

GnomAD3 genomes AF: 0.0392 AC: 5970 AN: 152140 Hom.: 165 Cov.: 32

Gnomad AFR AF: 0.00889

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0314

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0809

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0567

Gnomad OTH AF: 0.0311

GnomAD2 exomes AF: 0.0406 AC: 9592 AN: 236074 AF XY: 0.0416

Gnomad AFR exome AF: 0.00726

Gnomad AMR exome AF: 0.0164

Gnomad ASJ exome AF: 0.0436

Gnomad EAS exome AF: 0.0000571

Gnomad FIN exome AF: 0.0796

Gnomad NFE exome AF: 0.0568

Gnomad OTH exome AF: 0.0428

GnomAD4 exome AF: 0.0501 AC: 73045 AN: 1458744 Hom.: 1954 Cov.: 33 AF XY: 0.0497 AC XY: 36095 AN XY: 725644

African (AFR) AF: 0.00777 AC: 260 AN: 33464

American (AMR) AF: 0.0183 AC: 813 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.0422 AC: 1097 AN: 26024

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39658

South Asian (SAS) AF: 0.0215 AC: 1847 AN: 86026

European-Finnish (FIN) AF: 0.0792 AC: 4113 AN: 51900

Middle Eastern (MID) AF: 0.0328 AC: 188 AN: 5728

European-Non Finnish (NFE) AF: 0.0559 AC: 62076 AN: 1111254

Other (OTH) AF: 0.0440 AC: 2645 AN: 60174

GnomAD4 genome AF: 0.0392 AC: 5968 AN: 152258 Hom.: 165 Cov.: 32 AF XY: 0.0395 AC XY: 2938 AN XY: 74450

African (AFR) AF: 0.00886 AC: 368 AN: 41540

American (AMR) AF: 0.0314 AC: 480 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 132 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0176 AC: 85 AN: 4828

European-Finnish (FIN) AF: 0.0809 AC: 859 AN: 10614

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0567 AC: 3854 AN: 68006

Other (OTH) AF: 0.0313 AC: 66 AN: 2110

Alfa AF: 0.0507 Hom.: 375

Bravo AF: 0.0349

ESP6500AA AF: 0.00688 AC: 25

ESP6500EA AF: 0.0505 AC: 402

ExAC AF: 0.0392 AC: 4675

Asia WGS AF: 0.00808 AC: 29 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	Hypertrophic cardiomyopathy (4)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiomyopathy, familial restrictive, 1 (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 2A (1)
-	-	1	Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome (1)
-	-	1	Hypertrophic cardiomyopathy 7 (1)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	11
DANN	Benign	0.93
FATHMM_MKL	Benign	0.66	D
MetaRNN	Benign	0.0021	T
PhyloP100		0.10
GERP RS		2.1
PromoterAI		0.0042	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3729711; hg19: chr19-55667647;