rs4727

Variant names:

• chr11-1938477-C-T
• rs4727
• NM_006757.4:c.762C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-1938477-C-T
• chr11-1938477-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006757.4(TNNT3):​c.762C>T​(p.Gly254Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,612,734 control chromosomes in the GnomAD database, including 19,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1561 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17770 hom.)
• Consequence: TNNT3 NM_006757.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -4.71
• Publications: 15 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 11-1938477-C-T is Benign according to our data. Variant chr11-1938477-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.71 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.319 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.762C>T	p.Gly254Gly	synonymous	Exon 16 of 16	NP_006748.1	P45378-2
	TNNT3	NM_001367846.1		c.795C>T	p.Gly265Gly	synonymous	Exon 18 of 18	NP_001354775.1	P45378-1
	TNNT3	NM_001363561.2		c.771C>T	p.Gly257Gly	synonymous	Exon 17 of 17	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.762C>T	p.Gly254Gly	synonymous	Exon 16 of 16	ENSP00000278317.6	P45378-2
	TNNT3	ENST00000381589.7	TSL:1	c.756C>T	p.Gly252Gly	synonymous	Exon 16 of 16	ENSP00000371001.3	P45378-6
	TNNT3	ENST00000381579.7	TSL:1	c.738C>T	p.Gly246Gly	synonymous	Exon 15 of 15	ENSP00000370991.3	P45378-4

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19278 AN: 152042 Hom.: 1562 Cov.: 33

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.141

GnomAD2 exomes AF: 0.147 AC: 36530 AN: 247790 AF XY: 0.150

Gnomad AFR exome AF: 0.0344

Gnomad AMR exome AF: 0.0791

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.342

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.149 AC: 217737 AN: 1460574 Hom.: 17770 Cov.: 32 AF XY: 0.149 AC XY: 108213 AN XY: 726610

African (AFR) AF: 0.0356 AC: 1192 AN: 33472

American (AMR) AF: 0.0824 AC: 3686 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4697 AN: 26114

East Asian (EAS) AF: 0.329 AC: 13054 AN: 39662

South Asian (SAS) AF: 0.102 AC: 8832 AN: 86250

European-Finnish (FIN) AF: 0.175 AC: 9205 AN: 52714

Middle Eastern (MID) AF: 0.165 AC: 951 AN: 5762

European-Non Finnish (NFE) AF: 0.151 AC: 167288 AN: 1111538

Other (OTH) AF: 0.146 AC: 8832 AN: 60352

GnomAD4 genome AF: 0.127 AC: 19274 AN: 152160 Hom.: 1561 Cov.: 33 AF XY: 0.130 AC XY: 9645 AN XY: 74398

African (AFR) AF: 0.0385 AC: 1600 AN: 41528

American (AMR) AF: 0.107 AC: 1634 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 648 AN: 3472

East Asian (EAS) AF: 0.332 AC: 1706 AN: 5136

South Asian (SAS) AF: 0.110 AC: 530 AN: 4828

European-Finnish (FIN) AF: 0.188 AC: 1998 AN: 10606

Middle Eastern (MID) AF: 0.151 AC: 44 AN: 292

European-Non Finnish (NFE) AF: 0.157 AC: 10699 AN: 67976

Other (OTH) AF: 0.140 AC: 296 AN: 2112

Alfa AF: 0.124 Hom.: 1074

Bravo AF: 0.118

Asia WGS AF: 0.201 AC: 698 AN: 3478

EpiCase AF: 0.164

EpiControl AF: 0.167

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	3	not specified (3)
-	-	2	Distal arthrogryposis type 2B1 (2)
-	-	1	Arthrogryposis multiplex congenita distal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.7
DANN	Benign	0.77
PhyloP100		-4.7
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: rs4727; hg19: chr11-1959707; COSMIC: COSV53485519; COSMIC: COSV53485519;