11-1922883-C-G

Variant names:

• chr11-1922883-C-G
• rs750777064
• NM_006757.4:c.9C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006757.4(TNNT3):​c.9C>G​(p.Asp3Glu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT3 NM_006757.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.28

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3570012).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT3	NM_006757.4	c.9C>G	p.Asp3Glu	missense_variant	Exon 2 of 16	ENST00000278317.11	NP_006748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT3	ENST00000278317.11	c.9C>G	p.Asp3Glu	missense_variant	Exon 2 of 16	5	NM_006757.4	ENSP00000278317.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;T;.;.;.;.;.;.;.;.;T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.66	T;T;T;.;T;T;T;.;T;T;T;T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.74	N;N;N;N;N;N;N;N;.;.;N;N;N
REVEL	Benign	0.087
Sift	Benign	0.24	T;D;D;D;D;D;T;D;.;.;T;D;D
Sift4G	Benign	0.59	T;T;T;T;T;T;T;T;.;.;T;T;T
Polyphen		0.89	P;.;.;P;P;.;.;P;P;P;P;.;.
Vest4		0.43
MutPred		0.20		Loss of helix (P = 0.5774);Loss of helix (P = 0.5774);Loss of helix (P = 0.5774);Loss of helix (P = 0.5774);Loss of helix (P = 0.5774);Loss of helix (P = 0.5774);Loss of helix (P = 0.5774);Loss of helix (P = 0.5774);Loss of helix (P = 0.5774);Loss of helix (P = 0.5774);Loss of helix (P = 0.5774);Loss of helix (P = 0.5774);Loss of helix (P = 0.5774);
MVP		0.99
MPC		0.31
ClinPred		0.95	D
GERP RS		3.2
Varity_R		0.077
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs750777064; hg19: chr11-1944113;