11-1922820-CCTCTCTCTCT-CCTCTCTCT

Variant names:

• chr11-1922820-CCT-C
• rs140086507
• NM_006757.4:c.-18-18_-18-17delCT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001367847.1(TNNT3):​c.-36_-35delCT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000891 in 148,076 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 31)
  • Exomes 𝑓: 0.17 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNNT3 NM_001367847.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.77
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• arthrogryposis, distal, type 2B2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia
• distal arthrogryposis type 2B1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy

  Inheritance: AR Classification: STRONG Submitted by: G2P
• nemaline myopathy

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• digitotalar dysmorphism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sheldon-hall syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367847.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT3	NM_006757.4	MANE Select	c.-18-18_-18-17delCT		intron	N/A	NP_006748.1	P45378-2
	TNNT3	NM_001367847.1		c.-36_-35delCT		5_prime_UTR	Exon 1 of 16	NP_001354776.1	P45378-3
	TNNT3	NM_001367842.1		c.-36_-35delCT		5_prime_UTR	Exon 1 of 15	NP_001354771.1	P45378-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT3	ENST00000278317.11	TSL:5 MANE Select	c.-18-18_-18-17delCT		intron	N/A	ENSP00000278317.6	P45378-2
	TNNT3	ENST00000381589.7	TSL:1	c.-18-18_-18-17delCT		intron	N/A	ENSP00000371001.3	P45378-6
	TNNT3	ENST00000381579.7	TSL:1	c.-18-18_-18-17delCT		intron	N/A	ENSP00000370991.3	P45378-4

Frequencies

GnomAD3 genomes AF: 0.000892 AC: 132 AN: 147982 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000470

Gnomad ASJ AF: 0.000293

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.00526

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000946

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.174 AC: 122733 AN: 707142 Hom.: 0 AF XY: 0.178 AC XY: 60739 AN XY: 340626

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0702 AC: 1527 AN: 21742

American (AMR) AF: 0.193 AC: 3103 AN: 16092

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 2192 AN: 9356

East Asian (EAS) AF: 0.188 AC: 2444 AN: 13008

South Asian (SAS) AF: 0.258 AC: 7146 AN: 27664

European-Finnish (FIN) AF: 0.143 AC: 3070 AN: 21424

Middle Eastern (MID) AF: 0.102 AC: 338 AN: 3326

European-Non Finnish (NFE) AF: 0.173 AC: 97987 AN: 566972

Other (OTH) AF: 0.179 AC: 4926 AN: 27558

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000891 AC: 132 AN: 148076 Hom.: 0 Cov.: 31 AF XY: 0.000984 AC XY: 71 AN XY: 72176

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000245 AC: 10 AN: 40764

American (AMR) AF: 0.000470 AC: 7 AN: 14904

Ashkenazi Jewish (ASJ) AF: 0.000293 AC: 1 AN: 3412

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.000420 AC: 2 AN: 4764

European-Finnish (FIN) AF: 0.00526 AC: 49 AN: 9312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000946 AC: 63 AN: 66576

Other (OTH) AF: 0.00 AC: 0 AN: 2044

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000115 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs140086507; hg19: chr11-1944050; COSMIC: COSV53485726; COSMIC: COSV53485726;