11-1923560-T-C

Position:

• chr11-1923560-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_006757.4(TNNT3):​c.37T>C​(p.Tyr13His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Y13Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TNNT3 NM_006757.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a region_of_interest Disordered (size 71) in uniprot entity TNNT3_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_006757.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25130427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT3	NM_006757.4	c.37T>C	p.Tyr13His	missense_variant	4/16	ENST00000278317.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT3	ENST00000278317.11	c.37T>C	p.Tyr13His	missense_variant	4/16	5	NM_006757.4	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arthrogryposis, distal, type 2B2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant c.37T>Cp.Tyr13His in the TNNT3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. The amino acid Tyrosine at position 13 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Tyr13His in TNNT3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;T;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.69	T;T;.;T;T;T;.;T;T;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.82	D
MutationTaster	Benign	0.56	D;D;D;D;D;D;D;N;N;N;N;N;N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.58	N;N;N;N;N;N;N;.;.;N
REVEL	Uncertain	0.35
Sift	Benign	0.24	T;T;T;T;T;T;T;.;.;D
Sift4G	Benign	0.24	T;T;T;T;T;T;T;.;.;T
Polyphen		0.89	P;.;P;P;.;.;P;P;P;D
Vest4		0.36
MutPred		0.24		Loss of phosphorylation at Y13 (P = 0.0091);Loss of phosphorylation at Y13 (P = 0.0091);Loss of phosphorylation at Y13 (P = 0.0091);Loss of phosphorylation at Y13 (P = 0.0091);Loss of phosphorylation at Y13 (P = 0.0091);Loss of phosphorylation at Y13 (P = 0.0091);Loss of phosphorylation at Y13 (P = 0.0091);Loss of phosphorylation at Y13 (P = 0.0091);Loss of phosphorylation at Y13 (P = 0.0091);Loss of phosphorylation at Y13 (P = 0.0091);
MVP		0.97
MPC		0.44
ClinPred		0.75	D
GERP RS		3.6
Varity_R		0.12
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-1944790;