rs1190447904

Variant names:

• chr19-55157054-G-A
• rs1190447904
• NM_000363.5:c.104C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-55157054-G-A
• chr19-55157054-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000363.5(TNNI3):​c.104C>T​(p.Ala35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000834 in 1,438,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A35T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.28
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae)
• 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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 33 uncertain in NM_000363.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.24603307).

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.104C>T	p.Ala35Val	missense	Exon 3 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.104C>T	p.Ala35Val	missense	Exon 3 of 8	ENSP00000341838.5	P19429
	ENSG00000267110	ENST00000587871.1	TSL:5	n.*206C>T		non_coding_transcript_exon	Exon 6 of 9	ENSP00000473050.1	M0R381
	ENSG00000267110	ENST00000587871.1	TSL:5	n.*206C>T		3_prime_UTR	Exon 6 of 9	ENSP00000473050.1	M0R381

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000473 AC: 1 AN: 211604 AF XY: 0.00000877

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000189

GnomAD4 exome AF: 0.00000834 AC: 12 AN: 1438750 Hom.: 0 Cov.: 33 AF XY: 0.00000981 AC XY: 7 AN XY: 713310

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 39582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25566

East Asian (EAS) AF: 0.00 AC: 0 AN: 38988

South Asian (SAS) AF: 0.00 AC: 0 AN: 82108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50774

Middle Eastern (MID) AF: 0.000200 AC: 1 AN: 5006

European-Non Finnish (NFE) AF: 0.00000815 AC: 9 AN: 1103680

Other (OTH) AF: 0.0000335 AC: 2 AN: 59692

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hypertrophic cardiomyopathy (2)
-	1	-	Cardiomyopathy (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Hypertrophic cardiomyopathy 7;C1861861:Cardiomyopathy, familial restrictive, 1;C2678474:Dilated cardiomyopathy 2A;C2750091:Dilated cardiomyopathy 1FF (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
CardioboostCm	Benign	0.043
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.68	N
PhyloP100		1.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.40	N
REVEL	Uncertain	0.37
Sift	Benign	0.34	T
Sift4G	Benign	0.31	T
Polyphen		0.010	B
Vest4		0.21
MutPred		0.18		Gain of relative solvent accessibility (P = 0.0483)
MVP		0.91
MPC		0.66
ClinPred		0.22	T
GERP RS		3.0
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
Mutation Taster		=79/21	polymorphism

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: rs1190447904; hg19: chr19-55668422;