11-1920716-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	UniProt
TNNT3	NM_006757.4	c.-19+954T>C		intron_variant		ENST00000278317.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT3	ENST00000278317.11	c.-19+954T>C		intron_variant		5	NM_006757.4	A2

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

Gnomad4 AFR AF: 0.292

Gnomad4 AMR AF: 0.570

Gnomad4 ASJ AF: 0.436

Gnomad4 EAS AF: 0.637

Gnomad4 SAS AF: 0.361

Gnomad4 FIN AF: 0.560

Gnomad4 NFE AF: 0.475

Gnomad4 OTH AF: 0.462

Alfa AF: 0.471 Hom.: 32082

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

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