11-1922820-CCTCTCTCTCT-CCTCTCTCTCTCTCT

Variant names:

• chr11-1922820-C-CCTCT
• rs140086507
• NM_006757.4:c.-18-20_-18-17dupCTCT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001367847.1(TNNT3):​c.-38_-35dupCTCT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 1,465,150 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: TNNT3 NM_001367847.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 345 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT3	NM_006757.4	c.-18-20_-18-17dupCTCT		intron_variant	Intron 1 of 15	ENST00000278317.11	NP_006748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT3	ENST00000278317.11	c.-18-20_-18-17dupCTCT		intron_variant	Intron 1 of 15	5	NM_006757.4	ENSP00000278317.6

Frequencies

GnomAD3 genomes AF: 0.00228 AC: 341 AN: 149436 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00793

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000932

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: 0.0000298

Gnomad OTH AF: 0.000981

GnomAD4 exome AF: 0.000277 AC: 365 AN: 1315612 Hom.: 0 Cov.: 0 AF XY: 0.000258 AC XY: 170 AN XY: 658520

Gnomad4 AFR exome AF: 0.00768

Gnomad4 AMR exome AF: 0.000587

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000271

Gnomad4 SAS exome AF: 0.000194

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.000782

GnomAD4 genome AF: 0.00231 AC: 345 AN: 149538 Hom.: 2 Cov.: 31 AF XY: 0.00226 AC XY: 165 AN XY: 72984

Gnomad4 AFR AF: 0.00800

Gnomad4 AMR AF: 0.000931

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000298

Gnomad4 OTH AF: 0.000971

ClinVar

Not reported in ClinVar

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;