rs181586935

chr11-1929878-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006757.4(TNNT3):c.125+50G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 1,503,826 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (64 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (83 hom.)
• Consequence: TNNT3 NM_006757.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.30

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 11-1929878-G-C is Benign according to our data. Variant chr11-1929878-G-C is described in ClinVar as [Benign]. Clinvar id is 260024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT3	NM_006757.4	c.125+50G>C		intron_variant		ENST00000278317.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT3	ENST00000278317.11	c.125+50G>C		intron_variant		5	NM_006757.4	A2

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2510 AN: 145220 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0591

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000456

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0195

Gnomad NFE AF: 0.000725

Gnomad OTH AF: 0.0164

GnomAD3 exomes AF: 0.00439 AC: 683 AN: 155698 Hom.: 15 AF XY: 0.00352 AC XY: 288 AN XY: 81874

Gnomad AFR exome AF: 0.0533

Gnomad AMR exome AF: 0.00619

Gnomad ASJ exome AF: 0.000352

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000442

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000533

Gnomad OTH exome AF: 0.00567

GnomAD4 exome AF: 0.00178 AC: 2419 AN: 1358508 Hom.: 83 Cov.: 35 AF XY: 0.00158 AC XY: 1055 AN XY: 668976

Gnomad4 AFR exome AF: 0.0516

Gnomad4 AMR exome AF: 0.00693

Gnomad4 ASJ exome AF: 0.0000804

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000403

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000343

Gnomad4 OTH exome AF: 0.00501

GnomAD4 genome AF: 0.0173 AC: 2520 AN: 145318 Hom.: 64 Cov.: 32 AF XY: 0.0162 AC XY: 1151 AN XY: 70918

Gnomad4 AFR AF: 0.0593

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000456

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000725

Gnomad4 OTH AF: 0.0163

Alfa AF: 0.0294 Hom.: 21

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.56
Dann	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs181586935; hg19: chr11-1951108;