rs16927166

chr11-1934874-T-Cchr11-1934874-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006757.4(TNNT3):c.636T>C(p.Ile212=) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -1.99

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 31871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1934874-T-C is described in Lovd as [Benign]. Variant chr11-1934874-T-C is described in Lovd as [Likely_benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT3	NM_006757.4	c.636T>C	p.Ile212=	synonymous_variant	14/16	ENST00000278317.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT3	ENST00000278317.11	c.636T>C	p.Ile212=	synonymous_variant	14/16	5	NM_006757.4	A2

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 5870 AN: 152182 Hom.: 251 Cov.: 33

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

GnomAD3 exomes AF: 0.0210 AC: 5280 AN: 251284 Hom.: 154 AF XY: 0.0212 AC XY: 2886 AN XY: 135868

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 SAS exome AF: 0.0463

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.: 33 AF XY: 0.0154 AC XY: 11230 AN XY: 726932

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.0141

Gnomad4 ASJ exome AF: 0.00585

Gnomad4 EAS exome AF: 0.00254

Gnomad4 SAS exome AF: 0.0450

Gnomad4 FIN exome AF: 0.00445

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.0193

GnomAD4 genome AF: 0.0387 AC: 5890 AN: 152300 Hom.: 253 Cov.: 33 AF XY: 0.0383 AC XY: 2850 AN XY: 74482

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0244

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.00598

Gnomad4 SAS AF: 0.0408

Gnomad4 FIN AF: 0.00744

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0169 Hom.: 69

Bravo AF: 0.0413

Asia WGS AF: 0.0330 AC: 115 AN: 3478

EpiCase AF: 0.0132

EpiControl AF: 0.0146

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2019	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (TNNT3)	Mar 18, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Distal arthrogryposis type 2B1 Benign:1

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. -

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	-0.93
Cadd	Benign	0.0020
Dann	Benign	0.52

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

Other links and lift over

dbSNP: rs16927166; hg19: chr11-1956104; COSMIC: COSV53485438; COSMIC: COSV53485438;