NM_000363.5:c.11+128T>C

Variant names:

• chr19-55157451-A-G
• rs11667847
• NM_000363.5:c.11+128T>C

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.11+128T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,573,404 control chromosomes in the GnomAD database, including 29,067 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4011 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25056 hom.)
• Consequence: TNNI3 NM_000363.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.90
• Publications: 9 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=-0.91).
• BP6: Variant 19-55157451-A-G is Benign according to our data. Variant chr19-55157451-A-G is described in ClinVar as Benign. ClinVar VariationId is 1290282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.32 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.11+128T>C		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.11+128T>C		intron	N/A	ENSP00000341838.5
	ENSG00000267110	ENST00000587871.1	TSL:5	n.*131+111T>C		intron	N/A	ENSP00000473050.1
	TNNI3	ENST00000665070.1		c.11+128T>C		intron	N/A	ENSP00000499482.1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33254 AN: 151756 Hom.: 4005 Cov.: 32

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.223

GnomAD4 exome AF: 0.183 AC: 259569 AN: 1421530 Hom.: 25056 Cov.: 26 AF XY: 0.186 AC XY: 131245 AN XY: 706214

African (AFR) AF: 0.335 AC: 10920 AN: 32618

American (AMR) AF: 0.113 AC: 4938 AN: 43630

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 4240 AN: 24712

East Asian (EAS) AF: 0.178 AC: 6990 AN: 39346

South Asian (SAS) AF: 0.275 AC: 23068 AN: 83974

European-Finnish (FIN) AF: 0.198 AC: 10364 AN: 52416

Middle Eastern (MID) AF: 0.264 AC: 1484 AN: 5618

European-Non Finnish (NFE) AF: 0.172 AC: 185903 AN: 1080450

Other (OTH) AF: 0.198 AC: 11662 AN: 58766

GnomAD4 genome AF: 0.219 AC: 33288 AN: 151874 Hom.: 4011 Cov.: 32 AF XY: 0.219 AC XY: 16243 AN XY: 74252

African (AFR) AF: 0.325 AC: 13446 AN: 41396

American (AMR) AF: 0.154 AC: 2357 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 601 AN: 3470

East Asian (EAS) AF: 0.213 AC: 1092 AN: 5136

South Asian (SAS) AF: 0.280 AC: 1348 AN: 4810

European-Finnish (FIN) AF: 0.199 AC: 2098 AN: 10554

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.172 AC: 11667 AN: 67912

Other (OTH) AF: 0.225 AC: 476 AN: 2112

Alfa AF: 0.192 Hom.: 370

Bravo AF: 0.219

Asia WGS AF: 0.264 AC: 916 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	-0.91
CADD	Benign	1.5
DANN	Benign	0.15
PhyloP100		-1.9
PromoterAI		-0.080	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs11667847; hg19: chr19-55668819; COSMIC: COSV61276040; COSMIC: COSV61276040;