rs3729836

Variant names:

• chr19-55157141-A-T
• rs3729836
• NM_000363.5:c.25-8T>A

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.25-8T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,595,860 control chromosomes in the GnomAD database, including 61,446 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (11970 hom., cov: 31)
  • Exomes 𝑓: 0.24 (49476 hom.)
• Consequence: TNNI3 NM_000363.5 splice_region, intron
• Scores: Splicing: ADA: 0.002082
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: -1.35
• Publications: 18 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, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• dilated cardiomyopathy 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• cardiomyopathy, familial restrictive, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD, AR Classification: STRONG Submitted by: ClinGen
• dilated cardiomyopathy 1FF

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 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=-0.93).
• BP6: Variant 19-55157141-A-T is Benign according to our data. Variant chr19-55157141-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.606 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.25-8T>A		splice_region 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.25-8T>A		splice_region intron	N/A	ENSP00000341838.5	P19429
	ENSG00000267110	ENST00000587871.1	TSL:5	n.*132-13T>A		intron	N/A	ENSP00000473050.1	M0R381
	TNNI3	ENST00000665070.1		c.25-8T>A		splice_region intron	N/A	ENSP00000499482.1	A0A590UJN1

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53463 AN: 151578 Hom.: 11930 Cov.: 31

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.353

GnomAD2 exomes AF: 0.316 AC: 68587 AN: 216832 AF XY: 0.309

Gnomad AFR exome AF: 0.624

Gnomad AMR exome AF: 0.487

Gnomad ASJ exome AF: 0.212

Gnomad EAS exome AF: 0.425

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.242 AC: 348815 AN: 1444164 Hom.: 49476 Cov.: 35 AF XY: 0.245 AC XY: 175355 AN XY: 716598

African (AFR) AF: 0.631 AC: 21083 AN: 33400

American (AMR) AF: 0.481 AC: 19389 AN: 40342

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 5480 AN: 25648

East Asian (EAS) AF: 0.421 AC: 16475 AN: 39102

South Asian (SAS) AF: 0.413 AC: 34299 AN: 83060

European-Finnish (FIN) AF: 0.231 AC: 12055 AN: 52174

Middle Eastern (MID) AF: 0.328 AC: 1755 AN: 5354

European-Non Finnish (NFE) AF: 0.200 AC: 221582 AN: 1105220

Other (OTH) AF: 0.279 AC: 16697 AN: 59864

GnomAD4 genome AF: 0.353 AC: 53569 AN: 151696 Hom.: 11970 Cov.: 31 AF XY: 0.355 AC XY: 26325 AN XY: 74090

African (AFR) AF: 0.612 AC: 25328 AN: 41352

American (AMR) AF: 0.400 AC: 6101 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 743 AN: 3468

East Asian (EAS) AF: 0.440 AC: 2246 AN: 5104

South Asian (SAS) AF: 0.441 AC: 2113 AN: 4794

European-Finnish (FIN) AF: 0.227 AC: 2398 AN: 10554

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

European-Non Finnish (NFE) AF: 0.201 AC: 13663 AN: 67862

Other (OTH) AF: 0.360 AC: 755 AN: 2100

Alfa AF: 0.243 Hom.: 1792

Bravo AF: 0.378

Asia WGS AF: 0.520 AC: 1806 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Cardiomyopathy (2)
-	-	2	Cardiomyopathy, familial restrictive, 1 (2)
-	-	2	Dilated cardiomyopathy 2A (2)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	2	Hypertrophic cardiomyopathy 7 (2)
-	-	1	Dilated Cardiomyopathy, Recessive (1)
-	-	1	Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome (1)
-	-	1	Familial restrictive cardiomyopathy (1)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.1
DANN	Benign	0.67
PhyloP100		-1.3
PromoterAI		0.0051	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0021
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.16		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: rs3729836; hg19: chr19-55668509; COSMIC: COSV61277049; COSMIC: COSV61277049;