11-1923564-A-G

Position:

• chr11-1923564-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_006757.4(TNNT3):​c.41A>G​(p.Glu14Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNNT3 NM_006757.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.797

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 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT3	NM_006757.4	c.41A>G	p.Glu14Gly	missense_variant	4/16	ENST00000278317.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT3	ENST00000278317.11	c.41A>G	p.Glu14Gly	missense_variant	4/16	5	NM_006757.4	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461422 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 09, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 14 of the TNNT3 protein (p.Glu14Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TNNT3-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	.;T;.;.;.;.;.;.;.;D
Eigen	Benign	0.11
Eigen_PC	Benign	0.056
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.68	T;T;.;T;T;T;.;T;T;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.42	T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.8	D;N;N;N;D;N;N;.;.;D
REVEL	Uncertain	0.62
Sift	Benign	0.092	T;T;T;T;D;T;T;.;.;T
Sift4G	Uncertain	0.047	D;D;T;T;D;D;T;.;.;D
Polyphen		0.97	D;.;P;P;.;.;P;P;P;P
Vest4		0.38
MutPred		0.18		Loss of stability (P = 0.2186);Loss of stability (P = 0.2186);Loss of stability (P = 0.2186);Loss of stability (P = 0.2186);Loss of stability (P = 0.2186);Loss of stability (P = 0.2186);Loss of stability (P = 0.2186);Loss of stability (P = 0.2186);Loss of stability (P = 0.2186);Loss of stability (P = 0.2186);
MVP		0.99
MPC		0.39
ClinPred		0.91	D
GERP RS		3.6
Varity_R		0.26
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr11-1944794; COSMIC: COSV99548495; COSMIC: COSV99548495;