Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006757.4(TNNT3):c.636T>C(p.Ile212Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,613,608 control chromosomes in the GnomAD database, including 675 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 253 hom., cov: 33)

Exomes 𝑓: 0.015 ( 422 hom. )

Consequence

TNNT3
NM_006757.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -1.99

Publications

7 publications found

Variant links:

Genes affected

TNNT3 (HGNC:11950): (troponin T3, fast skeletal type) The binding of Ca(2+) to the trimeric troponin complex initiates the process of muscle contraction. Increased Ca(2+) concentrations produce a conformational change in the troponin complex that is transmitted to tropomyosin dimers situated along actin filaments. The altered conformation permits increased interaction between a myosin head and an actin filament which, ultimately, produces a muscle contraction. The troponin complex has protein subunits C, I, and T. Subunit C binds Ca(2+) and subunit I binds to actin and inhibits actin-myosin interaction. Subunit T binds the troponin complex to the tropomyosin complex and is also required for Ca(2+)-mediated activation of actomyosin ATPase activity. There are 3 different troponin T genes that encode tissue-specific isoforms of subunit T for fast skeletal-, slow skeletal-, and cardiac-muscle. This gene encodes fast skeletal troponin T protein; also known as troponin T type 3. Alternative splicing results in multiple transcript variants encoding additional distinct troponin T type 3 isoforms. A developmentally regulated switch between fetal/neonatal and adult troponin T type 3 isoforms occurs. Additional splice variants have been described but their biological validity has not been established. Mutations in this gene may cause distal arthrogryposis multiplex congenita type 2B (DA2B). [provided by RefSeq, Oct 2009]

TNNT3 Gene-Disease associations (from GenCC):

distal arthrogryposis type 2B1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
congenital myopathy
Inheritance: AR Classification: STRONG Submitted by: G2P
arthrogryposis, distal, type 2B2
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
nemaline myopathy
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen
digitotalar dysmorphism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Sheldon-hall syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TNNT3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 11-1934874-T-C is Benign according to our data. Variant chr11-1934874-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.99 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006757.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNNT3	NM_006757.4	MANE Select	c.636T>C	p.Ile212Ile	synonymous	Exon 14 of 16	NP_006748.1
TNNT3	NM_001367846.1		c.669T>C	p.Ile223Ile	synonymous	Exon 16 of 18	NP_001354775.1
TNNT3	NM_001363561.2		c.645T>C	p.Ile215Ile	synonymous	Exon 15 of 17	NP_001350490.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNNT3	ENST00000278317.11	TSL:5 MANE Select	c.636T>C	p.Ile212Ile	synonymous	Exon 14 of 16	ENSP00000278317.6
TNNT3	ENST00000381589.7	TSL:1	c.630T>C	p.Ile210Ile	synonymous	Exon 14 of 16	ENSP00000371001.3
TNNT3	ENST00000381579.7	TSL:1	c.612T>C	p.Ile204Ile	synonymous	Exon 13 of 15	ENSP00000370991.3

Frequencies

GnomAD3 genomes

AF:

0.0386

AC:

5870

AN:

152182

Hom.:

251

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0245

Gnomad ASJ

AF:

0.00894

Gnomad EAS

AF:

0.00597

Gnomad SAS

AF:

0.0410

Gnomad FIN

AF:

0.00744

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0122

Gnomad OTH

AF:

0.0316

GnomAD2 exomes

AF:

0.0210

AC:

5280

AN:

251284

AF XY:

0.0212

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.0133

Gnomad ASJ exome

AF:

0.00586

Gnomad EAS exome

AF:

0.00473

Gnomad FIN exome

AF:

0.00370

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.0188

GnomAD4 exome

AF:

0.0148

AC:

21577

AN:

1461308

Hom.:

422

Cov.:

AF XY:

0.0154

AC XY:

11230

AN XY:

726932

show subpopulations

African (AFR)

AF:

0.102

AC:

3403

AN:

33476

American (AMR)

AF:

0.0141

AC:

629

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00585

AC:

153

AN:

26136

East Asian (EAS)

AF:

0.00254

AC:

101

AN:

39700

South Asian (SAS)

AF:

0.0450

AC:

3884

AN:

86258

European-Finnish (FIN)

AF:

0.00445

AC:

235

AN:

52856

Middle Eastern (MID)

AF:

0.0354

AC:

204

AN:

5768

European-Non Finnish (NFE)

AF:

0.0106

AC:

11802

AN:

1112002

Other (OTH)

AF:

0.0193

AC:

1166

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1468

2936

4405

5873

7341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

520

1040

1560

2080

2600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0387

AC:

5890

AN:

152300

Hom.:

253

Cov.:

AF XY:

0.0383

AC XY:

2850

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.103

AC:

4272

AN:

41560

American (AMR)

AF:

0.0244

AC:

373

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00894

AC:

AN:

3466

East Asian (EAS)

AF:

0.00598

AC:

AN:

5184

South Asian (SAS)

AF:

0.0408

AC:

197

AN:

4830

European-Finnish (FIN)

AF:

0.00744

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0122

AC:

830

AN:

68014

Other (OTH)

AF:

0.0313

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

284

568

852

1136

1420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0185

Hom.:

179

Bravo

AF:

0.0413

Asia WGS

AF:

0.0330

AC:

115

AN:

3478

EpiCase

AF:

0.0132

EpiControl

AF:

0.0146

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Arthrogryposis multiplex congenita distal (1)

Distal arthrogryposis type 2B1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.0020

(source)

DANN

Benign

0.52

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs16927166

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over