11-1922885-A-T

Position:

chr11-1922885-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_006757.4(TNNT3):c.11A>T(p.Glu4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TNNT3
NM_006757.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.01

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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=0.33198056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT3	NM_006757.4 linkuse as main transcript	c.11A>T	p.Glu4Val	missense_variant	2/16	ENST00000278317.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT3	ENST00000278317.11 linkuse as main transcript	c.11A>T	p.Glu4Val	missense_variant	2/16	5	NM_006757.4	A2	P45378-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251192

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461422

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727054

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151956

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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 valine, which is neutral and non-polar, at codon 4 of the TNNT3 protein (p.Glu4Val). This variant is present in population databases (rs780143869, gnomAD 0.002%). 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

0.25

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.35

.;T;.;.;.;.;.;.;.;.;T;.;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.72

T;T;T;.;T;T;T;.;T;T;T;T;T

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.33

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.8

N;D;N;N;N;N;N;N;.;.;N;N;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.018

D;D;D;D;T;D;D;T;.;.;T;T;T

Sift4G

Uncertain

0.042

D;D;D;D;D;D;D;D;.;.;D;D;D

Polyphen

0.89

P;.;.;P;P;.;.;P;P;P;P;.;.

Vest4

0.47

MutPred

0.11

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

0.39

ClinPred

0.88

GERP RS

3.2

Varity_R

0.15

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over