chr19-55157029-C-T

Variant names:

• chr19-55157029-C-T
• rs3729837
• NM_000363.5:c.108+21G>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.108+21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0664 in 1,570,564 control chromosomes in the GnomAD database, including 4,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (278 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3722 hom.)
• Consequence: TNNI3 NM_000363.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.556
• Publications: 4 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=-0.72).
• BP6: Variant 19-55157029-C-T is Benign according to our data. Variant chr19-55157029-C-T is described in ClinVar as Benign. ClinVar VariationId is 255944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0967 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.108+21G>A		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.108+21G>A		intron	N/A	ENSP00000341838.5
	ENSG00000267110	ENST00000587871.1	TSL:5	n.*210+21G>A		intron	N/A	ENSP00000473050.1
	TNNI3	ENST00000665070.1		c.108+21G>A		intron	N/A	ENSP00000499482.1

Frequencies

GnomAD3 genomes AF: 0.0513 AC: 7796 AN: 151996 Hom.: 280 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0413

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.0425

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0595

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0688

Gnomad OTH AF: 0.0699

GnomAD2 exomes AF: 0.0662 AC: 12169 AN: 183920 AF XY: 0.0711

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.0379

Gnomad ASJ exome AF: 0.0958

Gnomad EAS exome AF: 0.0449

Gnomad FIN exome AF: 0.0571

Gnomad NFE exome AF: 0.0706

Gnomad OTH exome AF: 0.0869

GnomAD4 exome AF: 0.0680 AC: 96472 AN: 1418450 Hom.: 3722 Cov.: 33 AF XY: 0.0699 AC XY: 49041 AN XY: 701526

African (AFR) AF: 0.0122 AC: 405 AN: 33190

American (AMR) AF: 0.0375 AC: 1377 AN: 36714

Ashkenazi Jewish (ASJ) AF: 0.0937 AC: 2373 AN: 25324

East Asian (EAS) AF: 0.0251 AC: 969 AN: 38664

South Asian (SAS) AF: 0.110 AC: 8869 AN: 80882

European-Finnish (FIN) AF: 0.0628 AC: 2942 AN: 46836

Middle Eastern (MID) AF: 0.155 AC: 708 AN: 4566

European-Non Finnish (NFE) AF: 0.0681 AC: 74415 AN: 1093254

Other (OTH) AF: 0.0748 AC: 4414 AN: 59020

GnomAD4 genome AF: 0.0512 AC: 7788 AN: 152114 Hom.: 278 Cov.: 32 AF XY: 0.0516 AC XY: 3834 AN XY: 74374

African (AFR) AF: 0.0123 AC: 509 AN: 41506

American (AMR) AF: 0.0411 AC: 629 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0968 AC: 336 AN: 3470

East Asian (EAS) AF: 0.0422 AC: 218 AN: 5170

South Asian (SAS) AF: 0.104 AC: 502 AN: 4818

European-Finnish (FIN) AF: 0.0595 AC: 632 AN: 10616

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.0688 AC: 4673 AN: 67934

Other (OTH) AF: 0.0697 AC: 147 AN: 2110

Alfa AF: 0.0654 Hom.: 75

Bravo AF: 0.0460

Asia WGS AF: 0.0620 AC: 216 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.7
DANN	Benign	0.94
PhyloP100		-0.56
PromoterAI		0.037	Neutral
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3729837; hg19: chr19-55668397;