rs73413038

Positions:

• chr11-1934316-A-G

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.367-16A>G 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 0.0169 in 1,606,624 control chromosomes in the GnomAD database, including 657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (245 hom., cov: 33)
  • Exomes 𝑓: 0.015 (412 hom.)
• Consequence: TNNT3 NM_006757.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0940

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=-0.91).
• BP6: Variant 11-1934316-A-G is Benign according to our data. Variant chr11-1934316-A-G is described in ClinVar as [Benign]. Clinvar id is 260026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1934316-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT3	NM_006757.4	c.367-16A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000278317.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT3	ENST00000278317.11	c.367-16A>G		splice_polypyrimidine_tract_variant, intron_variant		5	NM_006757.4	A2

Frequencies

GnomAD3 genomes AF: 0.0381 AC: 5799 AN: 152088 Hom.: 243 Cov.: 33

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0244

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00599

Gnomad SAS AF: 0.0410

Gnomad FIN AF: 0.00745

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0208 AC: 5182 AN: 248538 Hom.: 142 AF XY: 0.0211 AC XY: 2848 AN XY: 134908

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.00582

Gnomad EAS exome AF: 0.00475

Gnomad SAS exome AF: 0.0464

Gnomad FIN exome AF: 0.00371

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0188

GnomAD4 exome AF: 0.0147 AC: 21400 AN: 1454418 Hom.: 412 Cov.: 32 AF XY: 0.0154 AC XY: 11161 AN XY: 724036

Gnomad4 AFR exome AF: 0.0996

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.00587

Gnomad4 EAS exome AF: 0.00252

Gnomad4 SAS exome AF: 0.0450

Gnomad4 FIN exome AF: 0.00445

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0382 AC: 5820 AN: 152206 Hom.: 245 Cov.: 33 AF XY: 0.0379 AC XY: 2818 AN XY: 74434

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0243

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.00601

Gnomad4 SAS AF: 0.0409

Gnomad4 FIN AF: 0.00745

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0228 Hom.: 25

Bravo AF: 0.0408

Asia WGS AF: 0.0330 AC: 115 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.1
DANN	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs73413038; hg19: chr11-1955546; COSMIC: COSV53485425; COSMIC: COSV53485425;