11-1922972-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006757.4(TNNT3):c.18-76A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.798 in 1,613,150 control chromosomes in the GnomAD database, including 516,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (43236 hom., cov: 32)
  • Exomes 𝑓: 0.80 (473669 hom.)
• Consequence: TNNT3 NM_006757.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -2.20

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 11-1922972-A-G is Benign according to our data. Variant chr11-1922972-A-G is described in ClinVar as [Benign]. Clinvar id is 31868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT3	NM_006757.4	c.18-76A>G		intron_variant		ENST00000278317.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT3	ENST00000278317.11	c.18-76A>G		intron_variant		5	NM_006757.4	A2

Frequencies

GnomAD3 genomes AF: 0.744 AC: 113028 AN: 151922 Hom.: 43225 Cov.: 32

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.807

Gnomad AMR AF: 0.833

Gnomad ASJ AF: 0.858

Gnomad EAS AF: 0.927

Gnomad SAS AF: 0.914

Gnomad FIN AF: 0.766

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.802

Gnomad OTH AF: 0.771

GnomAD4 exome AF: 0.803 AC: 1173479 AN: 1461110 Hom.: 473669 Cov.: 49 AF XY: 0.807 AC XY: 586961 AN XY: 726890

Gnomad4 AFR exome AF: 0.542

Gnomad4 AMR exome AF: 0.879

Gnomad4 ASJ exome AF: 0.852

Gnomad4 EAS exome AF: 0.928

Gnomad4 SAS exome AF: 0.912

Gnomad4 FIN exome AF: 0.766

Gnomad4 NFE exome AF: 0.795

Gnomad4 OTH exome AF: 0.804

GnomAD4 genome AF: 0.744 AC: 113084 AN: 152040 Hom.: 43236 Cov.: 32 AF XY: 0.748 AC XY: 55611 AN XY: 74316

Gnomad4 AFR AF: 0.554

Gnomad4 AMR AF: 0.834

Gnomad4 ASJ AF: 0.858

Gnomad4 EAS AF: 0.927

Gnomad4 SAS AF: 0.915

Gnomad4 FIN AF: 0.766

Gnomad4 NFE AF: 0.802

Gnomad4 OTH AF: 0.767

Alfa AF: 0.790 Hom.: 27439

Bravo AF: 0.737

Asia WGS AF: 0.854 AC: 2968 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (TNNT3)	Mar 18, 2012	- -

Arthrogryposis, distal, type 2B2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.54
Dann	Benign	0.54

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: rs965912; hg19: chr11-1944202; COSMIC: COSV53484474; COSMIC: COSV53484474;