rs3729707

Variant names:

• chr19-55157624-G-T
• rs3729707
• NM_000363.5:c.-35C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-55157624-G-T
• chr19-55157624-G-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.-35C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,613,762 control chromosomes in the GnomAD database, including 2,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene TNNI3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.069 (1133 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (1058 hom.)
• Consequence: TNNI3 NM_000363.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.615
• 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
• hypertrophic cardiomyopathy 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• dilated cardiomyopathy 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: AR, AD Classification: STRONG 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

Specifications for TNNI3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-55157624-G-T is Benign according to our data. Variant chr19-55157624-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.226 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.-35C>A		5_prime_UTR	Exon 1 of 8	NP_000354.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3	ENST00000344887.10	TSL:1 MANE Select	c.-35C>A		5_prime_UTR	Exon 1 of 8	ENSP00000341838.5	P19429
	ENSG00000267110	ENST00000587871.1	TSL:5	n.*69C>A		non_coding_transcript_exon	Exon 5 of 9	ENSP00000473050.1	M0R381
	ENSG00000267110	ENST00000587871.1	TSL:5	n.*69C>A		3_prime_UTR	Exon 5 of 9	ENSP00000473050.1	M0R381

Frequencies

GnomAD3 genomes AF: 0.0684 AC: 10397 AN: 152084 Hom.: 1126 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.0525

GnomAD2 exomes AF: 0.0196 AC: 4881 AN: 248884 AF XY: 0.0156

Gnomad AFR exome AF: 0.239

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.00649

Gnomad EAS exome AF: 0.00345

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00285

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.00892 AC: 13042 AN: 1461560 Hom.: 1058 Cov.: 32 AF XY: 0.00798 AC XY: 5800 AN XY: 727076

African (AFR) AF: 0.239 AC: 7983 AN: 33460

American (AMR) AF: 0.0169 AC: 754 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00666 AC: 174 AN: 26118

East Asian (EAS) AF: 0.00164 AC: 65 AN: 39700

South Asian (SAS) AF: 0.00458 AC: 395 AN: 86226

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53392

Middle Eastern (MID) AF: 0.0250 AC: 143 AN: 5712

European-Non Finnish (NFE) AF: 0.00204 AC: 2265 AN: 1111870

Other (OTH) AF: 0.0204 AC: 1234 AN: 60376

GnomAD4 genome AF: 0.0686 AC: 10436 AN: 152202 Hom.: 1133 Cov.: 32 AF XY: 0.0660 AC XY: 4916 AN XY: 74434

African (AFR) AF: 0.230 AC: 9552 AN: 41482

American (AMR) AF: 0.0307 AC: 469 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00483 AC: 25 AN: 5174

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4830

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10618

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00285 AC: 194 AN: 68014

Other (OTH) AF: 0.0558 AC: 118 AN: 2116

Alfa AF: 0.0279 Hom.: 90

Bravo AF: 0.0790

Asia WGS AF: 0.0550 AC: 192 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.8
DANN	Benign	0.79
PhyloP100		0.61
PromoterAI		-0.0073	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3729707;

hg19: chr19-55668992;