NM_000363.5:c.12-129A>G

Variant names:

• chr19-55157437-T-C
• rs11671293
• NM_000363.5:c.12-129A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000363.5(TNNI3):​c.12-129A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,580,076 control chromosomes in the GnomAD database, including 64,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (13194 hom., cov: 32)
  • Exomes 𝑓: 0.24 (50936 hom.)
• Consequence: TNNI3 NM_000363.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.130
• 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
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-55157437-T-C is Benign according to our data. Variant chr19-55157437-T-C is described in ClinVar as Benign. ClinVar VariationId is 1264197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.651 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.12-129A>G		intron	N/A	NP_000354.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3	ENST00000344887.10	TSL:1 MANE Select	c.12-129A>G		intron	N/A	ENSP00000341838.5
	ENSG00000267110	ENST00000587871.1	TSL:5	n.*131+125A>G		intron	N/A	ENSP00000473050.1
	TNNI3	ENST00000665070.1		c.12-129A>G		intron	N/A	ENSP00000499482.1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55478 AN: 151830 Hom.: 13154 Cov.: 32

Gnomad AFR AF: 0.657

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.360

GnomAD4 exome AF: 0.245 AC: 349428 AN: 1428128 Hom.: 50936 Cov.: 27 AF XY: 0.248 AC XY: 175709 AN XY: 709880

African (AFR) AF: 0.677 AC: 22182 AN: 32784

American (AMR) AF: 0.490 AC: 21374 AN: 43660

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 5329 AN: 24980

East Asian (EAS) AF: 0.421 AC: 16567 AN: 39370

South Asian (SAS) AF: 0.414 AC: 35031 AN: 84622

European-Finnish (FIN) AF: 0.231 AC: 12129 AN: 52494

Middle Eastern (MID) AF: 0.334 AC: 1885 AN: 5648

European-Non Finnish (NFE) AF: 0.201 AC: 218314 AN: 1085554

Other (OTH) AF: 0.282 AC: 16617 AN: 59016

GnomAD4 genome AF: 0.366 AC: 55586 AN: 151948 Hom.: 13194 Cov.: 32 AF XY: 0.367 AC XY: 27288 AN XY: 74274

African (AFR) AF: 0.658 AC: 27214 AN: 41388

American (AMR) AF: 0.404 AC: 6173 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 744 AN: 3472

East Asian (EAS) AF: 0.441 AC: 2273 AN: 5156

South Asian (SAS) AF: 0.440 AC: 2120 AN: 4816

European-Finnish (FIN) AF: 0.226 AC: 2398 AN: 10588

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13668 AN: 67946

Other (OTH) AF: 0.367 AC: 772 AN: 2106

Alfa AF: 0.303 Hom.: 5402

Bravo AF: 0.392

Asia WGS AF: 0.521 AC: 1809 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.8
DANN	Benign	0.57
PhyloP100		0.13
PromoterAI		-0.024	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs11671293; hg19: chr19-55668805; COSMIC: COSV61276034; COSMIC: COSV61276034;