NM_006757.4:c.367-16A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006757.4(TNNT3):c.367-16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,606,624 control chromosomes in the GnomAD database, including 657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 245 hom., cov: 33)

Exomes 𝑓: 0.015 ( 412 hom. )

Consequence

TNNT3
NM_006757.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0940

Publications

1 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):

arthrogryposis, distal, type 2B2
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia
distal arthrogryposis type 2B1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
congenital myopathy
Inheritance: AR Classification: STRONG Submitted by: G2P
nemaline myopathy
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 11-1934316-A-G is Benign according to our data. Variant chr11-1934316-A-G is described in ClinVar as Benign. ClinVar VariationId is 260026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0987 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	Effect	Exon Rank	Protein	UniProt
TNNT3	NM_006757.4	MANE Select	c.367-16A>G	intron	N/A	NP_006748.1	P45378-2
TNNT3	NM_001367846.1		c.400-16A>G	intron	N/A	NP_001354775.1	P45378-1
TNNT3	NM_001363561.2		c.376-16A>G	intron	N/A	NP_001350490.1	P45378-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TNNT3	ENST00000278317.11	TSL:5 MANE Select	c.367-16A>G	intron	N/A	ENSP00000278317.6	P45378-2
TNNT3	ENST00000381589.7	TSL:1	c.361-16A>G	intron	N/A	ENSP00000371001.3	P45378-6
TNNT3	ENST00000381579.7	TSL:1	c.343-16A>G	intron	N/A	ENSP00000370991.3	P45378-4

Frequencies

GnomAD3 genomes

AF:

0.0381

AC:

5799

AN:

152088

Hom.:

243

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0244

Gnomad ASJ

AF:

0.00894

Gnomad EAS

AF:

0.00599

Gnomad SAS

AF:

0.0410

Gnomad FIN

AF:

0.00745

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0122

Gnomad OTH

AF:

0.0316

GnomAD2 exomes

AF:

0.0208

AC:

5182

AN:

248538

AF XY:

0.0211

show subpopulations

Gnomad AFR exome

AF:

0.102

Gnomad AMR exome

AF:

0.0134

Gnomad ASJ exome

AF:

0.00582

Gnomad EAS exome

AF:

0.00475

Gnomad FIN exome

AF:

0.00371

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.0188

GnomAD4 exome

AF:

0.0147

AC:

21400

AN:

1454418

Hom.:

412

Cov.:

AF XY:

0.0154

AC XY:

11161

AN XY:

724036

show subpopulations

African (AFR)

AF:

0.0996

AC:

3322

AN:

33338

American (AMR)

AF:

0.0142

AC:

632

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00587

AC:

153

AN:

26072

East Asian (EAS)

AF:

0.00252

AC:

100

AN:

39642

South Asian (SAS)

AF:

0.0450

AC:

3874

AN:

86038

European-Finnish (FIN)

AF:

0.00445

AC:

236

AN:

53004

Middle Eastern (MID)

AF:

0.0352

AC:

203

AN:

5760

European-Non Finnish (NFE)

AF:

0.0106

AC:

11723

AN:

1105796

Other (OTH)

AF:

0.0192

AC:

1157

AN:

60110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1129

2258

3386

4515

5644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.0382

AC:

5820

AN:

152206

Hom.:

245

Cov.:

AF XY:

0.0379

AC XY:

2818

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.101

AC:

4206

AN:

41524

American (AMR)

AF:

0.0243

AC:

371

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00894

AC:

AN:

3466

East Asian (EAS)

AF:

0.00601

AC:

AN:

5162

South Asian (SAS)

AF:

0.0409

AC:

197

AN:

4822

European-Finnish (FIN)

AF:

0.00745

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0122

AC:

828

AN:

68010

Other (OTH)

AF:

0.0313

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

287

575

862

1150

1437

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:

0.0230

Hom.:

Bravo

AF:

0.0408

Asia WGS

AF:

0.0330

AC:

115

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.1

(source)

DANN

Benign

0.79

PhyloP100

0.094

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.

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

Computational scores

Splicing

Publications

Other links and lift over