11-1923557-C-A

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.34C>A(p.Gln12Lys) variant causes a missense, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TNNT3 NM_006757.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.254

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=0.1799708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT3	NM_006757.4	c.34C>A	p.Gln12Lys	missense_variant, splice_region_variant	4/16	ENST00000278317.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT3	ENST00000278317.11	c.34C>A	p.Gln12Lys	missense_variant, splice_region_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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 17, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TNNT3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with lysine at codon 12 of the TNNT3 protein (p.Gln12Lys). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
Cadd	Benign	21
Dann	Benign	0.95
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.66	T;T;.;T;T;T;.;T;T;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationTaster	Benign	1.0	D;D;D;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.82	N;N;N;N;N;N;N;.;.;N
REVEL	Benign	0.068
Sift	Benign	0.22	T;T;T;T;D;T;T;.;.;D
Sift4G	Benign	0.22	T;T;T;T;T;T;T;.;.;T
Polyphen		0.0010	B;.;B;B;.;.;B;B;B;B
Vest4		0.25
MutPred		0.18		Gain of ubiquitination at Q12 (P = 0.0048);Gain of ubiquitination at Q12 (P = 0.0048);Gain of ubiquitination at Q12 (P = 0.0048);Gain of ubiquitination at Q12 (P = 0.0048);Gain of ubiquitination at Q12 (P = 0.0048);Gain of ubiquitination at Q12 (P = 0.0048);Gain of ubiquitination at Q12 (P = 0.0048);Gain of ubiquitination at Q12 (P = 0.0048);Gain of ubiquitination at Q12 (P = 0.0048);Gain of ubiquitination at Q12 (P = 0.0048);
MVP		0.97
MPC		0.43
ClinPred		0.25	T
GERP RS		0.21
Varity_R		0.25
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-1944787;