11-1934323-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006757.4(TNNT3):c.367-9T>C variant causes a splice polypyrimidine tract, 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_006757.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.03510
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.853

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 260027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1934323-T-C is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 1273 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT3	NM_006757.4	c.367-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000278317.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT3	ENST00000278317.11	c.367-9T>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_006757.4	A2

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

GnomAD3 exomes AF: 0.00940 AC: 2341 AN: 249040 Hom.: 17 AF XY: 0.00961 AC XY: 1299 AN XY: 135124

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 SAS exome AF: 0.00652

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

Gnomad4 AFR exome AF: 0.00138

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00609

Gnomad4 FIN exome AF: 0.0301

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00879

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

Gnomad4 AFR AF: 0.00157

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00751

Gnomad4 FIN AF: 0.0338

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.00378

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

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 15, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2021	- -

Arthrogryposis multiplex congenita Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Distal arthrogryposis type 2B1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	15
Dann	Benign	0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs76471485; hg19: chr11-1955553;