11-1934323-T-C

Variant names:

• chr11-1934323-T-C
• rs76471485
• NM_006757.4:c.367-9T>C

Variant summary

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

The NM_001367846.1(TNNT3):​c.400-9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,610,516 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (6 hom., cov: 33)
  • Exomes 𝑓: 0.010 (96 hom.)
• Consequence: TNNT3 NM_001367846.1 intron
• Scores: Splicing: ADA: 0.03510
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.853
• 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):

• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 11-1934323-T-C is Benign according to our data. Variant chr11-1934323-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367846.1. 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.367-9T>C		intron	N/A	NP_006748.1
	TNNT3	NM_001367846.1		c.400-9T>C		intron	N/A	NP_001354775.1
	TNNT3	NM_001363561.2		c.376-9T>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.367-9T>C		intron	N/A	ENSP00000278317.6
	TNNT3	ENST00000381589.7	TSL:1	c.361-9T>C		intron	N/A	ENSP00000371001.3
	TNNT3	ENST00000381579.7	TSL:1	c.343-9T>C		intron	N/A	ENSP00000370991.3

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 1273 AN: 151762 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00771

Gnomad FIN AF: 0.0338

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00940 AC: 2341 AN: 249040 AF XY: 0.00961

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0302

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.00988

GnomAD4 exome AF: 0.0105 AC: 15249 AN: 1458636 Hom.: 96 Cov.: 33 AF XY: 0.0102 AC XY: 7424 AN XY: 725874

African (AFR) AF: 0.00138 AC: 46 AN: 33430

American (AMR) AF: 0.00260 AC: 116 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00609 AC: 525 AN: 86162

European-Finnish (FIN) AF: 0.0301 AC: 1597 AN: 53052

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5764

European-Non Finnish (NFE) AF: 0.0112 AC: 12414 AN: 1109460

Other (OTH) AF: 0.00879 AC: 530 AN: 60296

GnomAD4 genome AF: 0.00837 AC: 1271 AN: 151880 Hom.: 6 Cov.: 33 AF XY: 0.00910 AC XY: 675 AN XY: 74212

African (AFR) AF: 0.00157 AC: 65 AN: 41424

American (AMR) AF: 0.00321 AC: 49 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00751 AC: 36 AN: 4792

European-Finnish (FIN) AF: 0.0338 AC: 356 AN: 10542

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0111 AC: 753 AN: 67936

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00900 Hom.: 3

Bravo AF: 0.00569

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00965

EpiControl AF: 0.00796

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.89
PhyloP100		0.85
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.035
dbscSNV1_RF	Benign	0.29
SpliceAI score (max)		0.11		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: rs76471485; hg19: chr11-1955553;