chr11-1929072-A-G

Variant names:

• chr11-1929072-A-G
• rs629990
• NM_006757.4:c.83-48A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006757.4(TNNT3):​c.83-48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 1,610,974 control chromosomes in the GnomAD database, including 525,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (49988 hom., cov: 34)
  • Exomes 𝑓: 0.81 (475606 hom.)
• Consequence: TNNT3 NM_006757.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.709
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 11-1929072-A-G is Benign according to our data. Variant chr11-1929072-A-G is described in ClinVar as Benign. ClinVar VariationId is 260032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.902 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT3	NM_006757.4	MANE Select	c.83-48A>G		intron	N/A	NP_006748.1	P45378-2
	TNNT3	NM_001367846.1		c.116-48A>G		intron	N/A	NP_001354775.1	P45378-1
	TNNT3	NM_001363561.2		c.116-738A>G		intron	N/A	NP_001350490.1	P45378-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT3	ENST00000278317.11	TSL:5 MANE Select	c.83-48A>G		intron	N/A	ENSP00000278317.6	P45378-2
	TNNT3	ENST00000381589.7	TSL:1	c.101-738A>G		intron	N/A	ENSP00000371001.3	P45378-6
	TNNT3	ENST00000381579.7	TSL:1	c.83-738A>G		intron	N/A	ENSP00000370991.3	P45378-4

Frequencies

GnomAD3 genomes AF: 0.809 AC: 123114 AN: 152106 Hom.: 49944 Cov.: 34

Gnomad AFR AF: 0.801

Gnomad AMI AF: 0.816

Gnomad AMR AF: 0.857

Gnomad ASJ AF: 0.717

Gnomad EAS AF: 0.924

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.813

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.833

GnomAD2 exomes AF: 0.811 AC: 202732 AN: 250064 AF XY: 0.803

Gnomad AFR exome AF: 0.798

Gnomad AMR exome AF: 0.890

Gnomad ASJ exome AF: 0.708

Gnomad EAS exome AF: 0.918

Gnomad FIN exome AF: 0.809

Gnomad NFE exome AF: 0.809

Gnomad OTH exome AF: 0.811

GnomAD4 exome AF: 0.806 AC: 1176185 AN: 1458750 Hom.: 475606 Cov.: 36 AF XY: 0.803 AC XY: 582616 AN XY: 725864

African (AFR) AF: 0.798 AC: 26694 AN: 33454

American (AMR) AF: 0.888 AC: 39714 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 18580 AN: 26118

East Asian (EAS) AF: 0.912 AC: 36197 AN: 39688

South Asian (SAS) AF: 0.706 AC: 60901 AN: 86228

European-Finnish (FIN) AF: 0.809 AC: 41838 AN: 51720

Middle Eastern (MID) AF: 0.813 AC: 4689 AN: 5768

European-Non Finnish (NFE) AF: 0.810 AC: 899246 AN: 1110724

Other (OTH) AF: 0.801 AC: 48326 AN: 60338

GnomAD4 genome AF: 0.809 AC: 123219 AN: 152224 Hom.: 49988 Cov.: 34 AF XY: 0.808 AC XY: 60162 AN XY: 74430

African (AFR) AF: 0.801 AC: 33282 AN: 41544

American (AMR) AF: 0.857 AC: 13116 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 2488 AN: 3472

East Asian (EAS) AF: 0.924 AC: 4771 AN: 5162

South Asian (SAS) AF: 0.717 AC: 3462 AN: 4826

European-Finnish (FIN) AF: 0.813 AC: 8626 AN: 10612

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.805 AC: 54723 AN: 67988

Other (OTH) AF: 0.835 AC: 1765 AN: 2114

Alfa AF: 0.800 Hom.: 27572

Bravo AF: 0.816

Asia WGS AF: 0.833 AC: 2897 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Arthrogryposis, distal, type 2B2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.50
DANN	Benign	0.23
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs629990; hg19: chr11-1950302; COSMIC: COSV53489975; COSMIC: COSV53489975;