rs67795913

Positions:

• chr19-55141929-A-C

Variant summary

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

The ENST00000588981.6(TNNT1):​c.129-9T>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 0.128 in 1,613,310 control chromosomes in the GnomAD database, including 14,052 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (966 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13086 hom.)
• Consequence: TNNT1 ENST00000588981.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.8072
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.256

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=-0.76).
• BP6: Variant 19-55141929-A-C is Benign according to our data. Variant chr19-55141929-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 130602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55141929-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT1	NM_003283.6	c.129-9T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000588981.6	NP_003274.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT1	ENST00000588981.6	c.129-9T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003283.6	ENSP00000467176

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15892 AN: 151960 Hom.: 966 Cov.: 31

Gnomad AFR AF: 0.0376

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.0845

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.120 AC: 30207 AN: 251244 Hom.: 2011 AF XY: 0.122 AC XY: 16575 AN XY: 135802

Gnomad AFR exome AF: 0.0337

Gnomad AMR exome AF: 0.0791

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.197

Gnomad SAS exome AF: 0.0849

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.131 AC: 191240 AN: 1461232 Hom.: 13086 Cov.: 31 AF XY: 0.130 AC XY: 94420 AN XY: 726928

Gnomad4 AFR exome AF: 0.0360

Gnomad4 AMR exome AF: 0.0808

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.193

Gnomad4 SAS exome AF: 0.0870

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.104 AC: 15882 AN: 152078 Hom.: 966 Cov.: 31 AF XY: 0.105 AC XY: 7807 AN XY: 74336

Gnomad4 AFR AF: 0.0374

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.183

Gnomad4 SAS AF: 0.0844

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.125

Alfa AF: 0.125 Hom.: 411

Bravo AF: 0.102

Asia WGS AF: 0.0980 AC: 341 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.129-9T>G in intron 6 of TNNT1: This variant is not expected to have clinical s ignificance because it has been identified in 14.6% (1253/8600) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs67795913). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 5 Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 09, 2015	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	11
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.81
dbscSNV1_RF	Benign	0.72
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs67795913; hg19: chr19-55653297;