11-1934874-T-G

Position:

• chr11-1934874-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006757.4(TNNT3):​c.636T>G​(p.Ile212Met) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I212I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNNT3 NM_006757.4 missense
• Clinical Significance: Not reported in ClinVar
• 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]

TNNT3 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060902894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT3	NM_006757.4	c.636T>G	p.Ile212Met	missense_variant	14/16	ENST00000278317.11	NP_006748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT3	ENST00000278317.11	c.636T>G	p.Ile212Met	missense_variant	14/16	5	NM_006757.4	ENSP00000278317.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.0010
DANN	Benign	0.87
DEOGEN2	Benign	0.26	.;T;.;.;.;.;.;.;.;.;.;T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.79	T;T;T;.;T;T;T;.;T;T;T;T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.061	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;N;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.14	N;N;N;N;N;N;N;N;.;.;.;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0080	D;D;D;D;D;D;D;D;.;.;.;D;D;D
Sift4G	Uncertain	0.035	D;T;T;T;T;D;T;T;.;.;.;D;T;T
Polyphen		0.027	B;.;.;B;B;.;.;B;B;B;.;B;.;.
Vest4		0.089
MutPred		0.20		.;.;.;.;.;.;.;.;.;.;.;Gain of disorder (P = 0.0563);.;.;
MVP		0.45
MPC		0.35
ClinPred		0.17	T
GERP RS		-8.6
Varity_R		0.069
gMVP		0.39

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;