NM_000363.5:c.108+108G>T

Variant names:

• chr19-55156942-C-A
• rs3729838
• NM_000363.5:c.108+108G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_000363.5(TNNI3):​c.108+108G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000765 in 1,281,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: TNNI3 NM_000363.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -7.55
• Publications: 7 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
• 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

ENSG00000267110 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000191 (29/152020) while in subpopulation AMR AF = 0.000916 (14/15278). AF 95% confidence interval is 0.000553. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3	NM_000363.5	c.108+108G>T		intron_variant	Intron 3 of 7	ENST00000344887.10	NP_000354.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10	c.108+108G>T		intron_variant	Intron 3 of 7	1	NM_000363.5	ENSP00000341838.5
ENSG00000267110	ENST00000587871.1	n.*210+108G>T		intron_variant	Intron 6 of 8	5		ENSP00000473050.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 151902 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

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: 0.00

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.0000611 AC: 69 AN: 1129058 Hom.: 0 Cov.: 16 AF XY: 0.0000459 AC XY: 26 AN XY: 566908

African (AFR) AF: 0.000566 AC: 15 AN: 26518

American (AMR) AF: 0.00108 AC: 38 AN: 35296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23502

East Asian (EAS) AF: 0.00 AC: 0 AN: 34514

South Asian (SAS) AF: 0.00 AC: 0 AN: 73828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3596

European-Non Finnish (NFE) AF: 0.00000826 AC: 7 AN: 847310

Other (OTH) AF: 0.000183 AC: 9 AN: 49276

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152020 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74302

African (AFR) AF: 0.000338 AC: 14 AN: 41438

American (AMR) AF: 0.000916 AC: 14 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67968

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00 Hom.: 169

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.014
DANN	Benign	0.50
PhyloP100		-7.6
PromoterAI		0.066	Neutral

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: rs3729838; hg19: chr19-55668310;