11-1938423-G-C

Variant names:

• chr11-1938423-G-C
• rs143255528
• NM_006757.4:c.723-15G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006757.4(TNNT3):​c.723-15G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00609 in 1,613,066 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (45 hom.)
• Consequence: TNNT3 NM_006757.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.441
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-1938423-G-C is Benign according to our data. Variant chr11-1938423-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.723-15G>C		intron	N/A	NP_006748.1	P45378-2
	TNNT3	NM_001367846.1		c.756-15G>C		intron	N/A	NP_001354775.1	P45378-1
	TNNT3	NM_001363561.2		c.732-15G>C		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.723-15G>C		intron	N/A	ENSP00000278317.6	P45378-2
	TNNT3	ENST00000381589.7	TSL:1	c.717-15G>C		intron	N/A	ENSP00000371001.3	P45378-6
	TNNT3	ENST00000381579.7	TSL:1	c.699-15G>C		intron	N/A	ENSP00000370991.3	P45378-4

Frequencies

GnomAD3 genomes AF: 0.00404 AC: 615 AN: 152214 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00329

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00672

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00407 AC: 1009 AN: 247882 AF XY: 0.00405

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.00695

Gnomad OTH exome AF: 0.00361

GnomAD4 exome AF: 0.00631 AC: 9214 AN: 1460734 Hom.: 45 Cov.: 30 AF XY: 0.00615 AC XY: 4472 AN XY: 726650

African (AFR) AF: 0.00111 AC: 37 AN: 33464

American (AMR) AF: 0.00150 AC: 67 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00188 AC: 162 AN: 86250

European-Finnish (FIN) AF: 0.00454 AC: 239 AN: 52594

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5758

European-Non Finnish (NFE) AF: 0.00758 AC: 8426 AN: 1111794

Other (OTH) AF: 0.00408 AC: 246 AN: 60358

GnomAD4 genome AF: 0.00404 AC: 616 AN: 152332 Hom.: 2 Cov.: 33 AF XY: 0.00369 AC XY: 275 AN XY: 74482

African (AFR) AF: 0.00118 AC: 49 AN: 41590

American (AMR) AF: 0.00137 AC: 21 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4830

European-Finnish (FIN) AF: 0.00329 AC: 35 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00672 AC: 457 AN: 68012

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00392

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Arthrogryposis multiplex congenita (1)
-	-	1	Arthrogryposis multiplex congenita distal (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	16
DANN	Benign	0.76
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs143255528; hg19: chr11-1959653;