chr11-1927731-T-C

Variant names:

• chr11-1927731-T-C
• rs2734510
• NM_006757.4:c.82+1022T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006757.4(TNNT3):​c.82+1022T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 152,120 control chromosomes in the GnomAD database, including 11,646 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (11628 hom., cov: 33)
  • Exomes 𝑓: 0.43 (18 hom.)
• Consequence: TNNT3 NM_006757.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.215
• Publications: 12 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):

• distal arthrogryposis type 2B1

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

  Inheritance: AR Classification: STRONG Submitted by: G2P
• arthrogryposis, distal, type 2B2

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• nemaline myopathy

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006757.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT3	NM_006757.4	MANE Select	c.82+1022T>C		intron	N/A	NP_006748.1
	TNNT3	NM_001367846.1		c.115+1022T>C		intron	N/A	NP_001354775.1
	TNNT3	NM_001363561.2		c.115+1022T>C		intron	N/A	NP_001350490.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT3	ENST00000278317.11	TSL:5 MANE Select	c.82+1022T>C		intron	N/A	ENSP00000278317.6
	TNNT3	ENST00000381589.7	TSL:1	c.100+1250T>C		intron	N/A	ENSP00000371001.3
	TNNT3	ENST00000381579.7	TSL:1	c.82+1022T>C		intron	N/A	ENSP00000370991.3

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59009 AN: 151770 Hom.: 11631 Cov.: 33

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.412

GnomAD4 exome AF: 0.431 AC: 100 AN: 232 Hom.: 18 AF XY: 0.397 AC XY: 54 AN XY: 136

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 2 AN: 8

East Asian (EAS) AF: 0.167 AC: 1 AN: 6

South Asian (SAS) AF: 0.400 AC: 4 AN: 10

European-Finnish (FIN) AF: 0.471 AC: 16 AN: 34

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.466 AC: 68 AN: 146

Other (OTH) AF: 0.292 AC: 7 AN: 24

GnomAD4 genome AF: 0.389 AC: 59039 AN: 151888 Hom.: 11628 Cov.: 33 AF XY: 0.383 AC XY: 28446 AN XY: 74220

African (AFR) AF: 0.368 AC: 15225 AN: 41400

American (AMR) AF: 0.329 AC: 5034 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 1229 AN: 3468

East Asian (EAS) AF: 0.280 AC: 1439 AN: 5148

South Asian (SAS) AF: 0.378 AC: 1823 AN: 4822

European-Finnish (FIN) AF: 0.368 AC: 3884 AN: 10562

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29059 AN: 67886

Other (OTH) AF: 0.416 AC: 877 AN: 2108

Alfa AF: 0.405 Hom.: 12127

Bravo AF: 0.384

Asia WGS AF: 0.333 AC: 1158 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.8
DANN	Benign	0.62
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs2734510; hg19: chr11-1948961;