rs11669534

chr19-55146720-G-Achr19-55146720-G-T

Variant summary

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

The NM_003283.6(TNNT1):c.47-13C>T 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 0.156 in 1,499,846 control chromosomes in the GnomAD database, including 20,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1416 hom., cov: 31)
  • Exomes 𝑓: 0.16 (19302 hom.)
• Consequence: TNNT1 NM_003283.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.0470

Genes affected

TNNT1 (HGNC:11948): (troponin T1, slow skeletal type) This gene encodes a protein that is a subunit of troponin, which is a regulatory complex located on the thin filament of the sarcomere. This complex regulates striated muscle contraction in response to fluctuations in intracellular calcium concentration. This complex is composed of three subunits: troponin C, which binds calcium, troponin T, which binds tropomyosin, and troponin I, which is an inhibitory subunit. This protein is the slow skeletal troponin T subunit. Mutations in this gene cause nemaline myopathy type 5, also known as Amish nemaline myopathy, a neuromuscular disorder characterized by muscle weakness and rod-shaped, or nemaline, inclusions in skeletal muscle fibers which affects infants, resulting in death due to respiratory insufficiency, usually in the second year. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 19-55146720-G-A is Benign according to our data. Variant chr19-55146720-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 31863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55146720-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT1	NM_003283.6	c.47-13C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000588981.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT1	ENST00000588981.6	c.47-13C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003283.6

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17915 AN: 151942 Hom.: 1414 Cov.: 31

Gnomad AFR AF: 0.0324

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.00291

Gnomad SAS AF: 0.0503

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.103

GnomAD3 exomes AF: 0.105 AC: 12796 AN: 121404 Hom.: 906 AF XY: 0.106 AC XY: 6770 AN XY: 64016

Gnomad AFR exome AF: 0.0208

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.000491

Gnomad SAS exome AF: 0.0530

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.161 AC: 216723 AN: 1347786 Hom.: 19302 Cov.: 32 AF XY: 0.158 AC XY: 104449 AN XY: 659544

Gnomad4 AFR exome AF: 0.0250

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.000560

Gnomad4 SAS exome AF: 0.0572

Gnomad4 FIN exome AF: 0.136

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.140

GnomAD4 genome AF: 0.118 AC: 17918 AN: 152060 Hom.: 1416 Cov.: 31 AF XY: 0.114 AC XY: 8497 AN XY: 74350

Gnomad4 AFR AF: 0.0324

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.00291

Gnomad4 SAS AF: 0.0508

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.102

Alfa AF: 0.0897 Hom.: 191

Bravo AF: 0.114

Asia WGS AF: 0.0390 AC: 135 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	c.47-13C>T in intron 3 of TNNT1: This variant is not expected to have clinical s ignificance because it has been identified in 14% (985/6886) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs11669534). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 5 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 24, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided Other:1

not provided, no classification provided

curation

Leiden Muscular Dystrophy (TNNT1)

Mar 18, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	12
Dann	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs11669534; hg19: chr19-55658088;