11-1920716-T-C

Variant names:

• chr11-1920716-T-C
• rs909116
• NM_006757.4:c.-19+954T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006757.4(TNNT3):​c.-19+954T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 151,904 control chromosomes in the GnomAD database, including 15,567 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.44 (15567 hom., cov: 32)
• Consequence: TNNT3 NM_006757.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0430
• Publications: 58 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT3	NM_006757.4	c.-19+954T>C		intron_variant	Intron 1 of 15	ENST00000278317.11	NP_006748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT3	ENST00000278317.11	c.-19+954T>C		intron_variant	Intron 1 of 15	5	NM_006757.4	ENSP00000278317.6

Frequencies

GnomAD3 genomes AF: 0.441 AC: 66998 AN: 151790 Hom.: 15557 Cov.: 32

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.527

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.459

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.441 AC: 67045 AN: 151904 Hom.: 15567 Cov.: 32 AF XY: 0.445 AC XY: 33044 AN XY: 74244

African (AFR) AF: 0.292 AC: 12090 AN: 41404

American (AMR) AF: 0.570 AC: 8705 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1512 AN: 3468

East Asian (EAS) AF: 0.637 AC: 3280 AN: 5152

South Asian (SAS) AF: 0.361 AC: 1736 AN: 4814

European-Finnish (FIN) AF: 0.560 AC: 5911 AN: 10554

Middle Eastern (MID) AF: 0.339 AC: 99 AN: 292

European-Non Finnish (NFE) AF: 0.475 AC: 32256 AN: 67922

Other (OTH) AF: 0.462 AC: 975 AN: 2110

Alfa AF: 0.467 Hom.: 71344

Bravo AF: 0.441

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.9
DANN	Benign	0.55
PhyloP100		0.043
Mutation Taster		=100/0	polymorphism (auto)

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: rs909116; hg19: chr11-1941946; COSMIC: COSV53484459;