11-1938477-C-T

Position:

chr11-1938477-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_006757.4(TNNT3):c.762C>T(p.Gly254=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,612,734 control chromosomes in the GnomAD database, including 19,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1561 hom., cov: 33)

Exomes 𝑓: 0.15 ( 17770 hom. )

Consequence

TNNT3
NM_006757.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -4.71

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 11-1938477-C-T is Benign according to our data. Variant chr11-1938477-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 31872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1938477-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.71 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT3	NM_006757.4 linkuse as main transcript	c.762C>T	p.Gly254=	synonymous_variant	16/16	ENST00000278317.11	NP_006748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT3	ENST00000278317.11 linkuse as main transcript	c.762C>T	p.Gly254=	synonymous_variant	16/16	5	NM_006757.4	ENSP00000278317	A2	P45378-2

Frequencies

GnomAD3 genomes

AF:

0.127

AC:

19278

AN:

152042

Hom.:

1562

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0385

Gnomad AMI

AF:

0.131

Gnomad AMR

AF:

0.107

Gnomad ASJ

AF:

0.187

Gnomad EAS

AF:

0.332

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.188

Gnomad MID

AF:

0.159

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.141

GnomAD3 exomes

AF:

0.147

AC:

36530

AN:

247790

Hom.:

3436

AF XY:

0.150

AC XY:

20231

AN XY:

134540

show subpopulations

Gnomad AFR exome

AF:

0.0344

Gnomad AMR exome

AF:

0.0791

Gnomad ASJ exome

AF:

0.182

Gnomad EAS exome

AF:

0.342

Gnomad SAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.183

Gnomad NFE exome

AF:

0.155

Gnomad OTH exome

AF:

0.152

GnomAD4 exome

AF:

0.149

AC:

217737

AN:

1460574

Hom.:

17770

Cov.:

AF XY:

0.149

AC XY:

108213

AN XY:

726610

show subpopulations

Gnomad4 AFR exome

AF:

0.0356

Gnomad4 AMR exome

AF:

0.0824

Gnomad4 ASJ exome

AF:

0.180

Gnomad4 EAS exome

AF:

0.329

Gnomad4 SAS exome

AF:

0.102

Gnomad4 FIN exome

AF:

0.175

Gnomad4 NFE exome

AF:

0.151

Gnomad4 OTH exome

AF:

0.146

GnomAD4 genome

AF:

0.127

AC:

19274

AN:

152160

Hom.:

1561

Cov.:

AF XY:

0.130

AC XY:

9645

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0385

Gnomad4 AMR

AF:

0.107

Gnomad4 ASJ

AF:

0.187

Gnomad4 EAS

AF:

0.332

Gnomad4 SAS

AF:

0.110

Gnomad4 FIN

AF:

0.188

Gnomad4 NFE

AF:

0.157

Gnomad4 OTH

AF:

0.140

Alfa

AF:

0.143

Hom.:

859

Bravo

AF:

0.118

Asia WGS

AF:

0.201

AC:

698

AN:

3478

EpiCase

AF:

0.164

EpiControl

AF:

0.167

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (TNNT3)	Mar 18, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Distal arthrogryposis type 2B1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Arthrogryposis multiplex congenita distal

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

6.7

DANN

Benign

0.77

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over