rs147535560

Variant names:

• chr11-1938528-C-T
• rs147535560
• NM_006757.4:c.*36C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-1938528-C-T
• chr11-1938528-C-A
• chr11-1938528-C-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.*36C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,605,742 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (78 hom.)
• Consequence: TNNT3 NM_006757.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.61
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 11-1938528-C-T is Benign according to our data. Variant chr11-1938528-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0516 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.*36C>T		3_prime_UTR	Exon 16 of 16	NP_006748.1	P45378-2
	TNNT3	NM_001367846.1		c.*36C>T		3_prime_UTR	Exon 18 of 18	NP_001354775.1	P45378-1
	TNNT3	NM_001363561.2		c.*36C>T		3_prime_UTR	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.*36C>T		3_prime_UTR	Exon 16 of 16	ENSP00000278317.6	P45378-2
	TNNT3	ENST00000381589.7	TSL:1	c.*36C>T		3_prime_UTR	Exon 16 of 16	ENSP00000371001.3	P45378-6
	TNNT3	ENST00000381579.7	TSL:1	c.*36C>T		3_prime_UTR	Exon 15 of 15	ENSP00000370991.3	P45378-4

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 416 AN: 152156 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00866 AC: 2099 AN: 242334 AF XY: 0.00620

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.0591

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000890

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000560

Gnomad OTH exome AF: 0.00622

GnomAD4 exome AF: 0.00181 AC: 2628 AN: 1453468 Hom.: 78 Cov.: 29 AF XY: 0.00149 AC XY: 1075 AN XY: 723448

African (AFR) AF: 0.000959 AC: 32 AN: 33360

American (AMR) AF: 0.0534 AC: 2374 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00225 AC: 89 AN: 39582

South Asian (SAS) AF: 0.0000698 AC: 6 AN: 86004

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52264

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.0000326 AC: 36 AN: 1105902

Other (OTH) AF: 0.00148 AC: 89 AN: 60062

GnomAD4 genome AF: 0.00274 AC: 417 AN: 152274 Hom.: 6 Cov.: 33 AF XY: 0.00269 AC XY: 200 AN XY: 74444

African (AFR) AF: 0.00147 AC: 61 AN: 41562

American (AMR) AF: 0.0214 AC: 328 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00310 AC: 16 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 67996

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000252 Hom.: 0

Bravo AF: 0.00575

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.74
DANN	Benign	0.50
PhyloP100		-2.6
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: rs147535560; hg19: chr11-1959758; COSMIC: COSV53487144; COSMIC: COSV53487144;