Variant 11-1923563-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_006757.4(TNNT3):c.40G>C(p.Glu14Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,613,354 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 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

TNNT3
NM_006757.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.38

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.321314).

BS2

High AC in GnomAdExome4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT3	NM_006757.4 link	c.40G>C	p.Glu14Gln	missense_variant	4/16	ENST00000278317.11	NP_006748.1	P45378-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT3	ENST00000278317.11 link	c.40G>C	p.Glu14Gln	missense_variant	4/16	5	NM_006757.4	ENSP00000278317.6		P45378-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251416

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

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:

0.0000479

AC:

AN:

1461408

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726988

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:

0.0000612

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151946

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Benign

0.90

DEOGEN2

Benign

0.31

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

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.69

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

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.32

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

MetaSVM

Pathogenic

1.1

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.1

N;N;N;N;N;N;N;.;.;N

REVEL

Uncertain

0.55

Sift

Benign

0.16

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

Sift4G

Benign

0.13

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

Polyphen

0.99

D;.;P;P;.;.;P;P;P;D

Vest4

0.37

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);

MVP

0.99

MPC

0.33

ClinPred

0.53

GERP RS

3.6

Varity_R

0.13

gMVP

0.60

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over