11-1922820-C-CCT

Position:

• chr11-1922820-C-CCT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_006757.4(TNNT3):​c.-18-18_-18-17dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,450,634 control chromosomes in the GnomAD database, including 991 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.063 (934 hom., cov: 31)
  • Exomes 𝑓: 0.0082 (57 hom.)
• Consequence: TNNT3 NM_006757.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.77

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 -10 ACMG points.

• BP6: Variant 11-1922820-C-CCT is Benign according to our data. Variant chr11-1922820-C-CCT is described in ClinVar as [Benign]. Clinvar id is 1250023.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT3	NM_006757.4	c.-18-18_-18-17dup		intron_variant		ENST00000278317.11	NP_006748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT3	ENST00000278317.11	c.-18-18_-18-17dup		intron_variant		5	NM_006757.4	ENSP00000278317	A2

Frequencies

GnomAD3 genomes AF: 0.0626 AC: 9348 AN: 149402 Hom.: 933 Cov.: 31

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0273

Gnomad ASJ AF: 0.0172

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00126

Gnomad FIN AF: 0.000101

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.0530

GnomAD4 exome AF: 0.00817 AC: 10631 AN: 1301130 Hom.: 57 Cov.: 0 AF XY: 0.00722 AC XY: 4707 AN XY: 651926

Gnomad4 AFR exome AF: 0.207

Gnomad4 AMR exome AF: 0.0188

Gnomad4 ASJ exome AF: 0.0173

Gnomad4 EAS exome AF: 0.000299

Gnomad4 SAS exome AF: 0.00158

Gnomad4 FIN exome AF: 0.000824

Gnomad4 NFE exome AF: 0.00190

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.0627 AC: 9367 AN: 149504 Hom.: 934 Cov.: 31 AF XY: 0.0605 AC XY: 4415 AN XY: 72966

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.0273

Gnomad4 ASJ AF: 0.0172

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00105

Gnomad4 FIN AF: 0.000101

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.0524

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 28, 2020

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140086507; hg19: chr11-1944050;