19-55147029-C-T

Position:

• chr19-55147029-C-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.33-8G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,611,684 control chromosomes in the GnomAD database, including 1,349 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (237 hom., cov: 32)
  • Exomes 𝑓: 0.030 (1112 hom.)
• Consequence: TNNT1 NM_003283.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.05309
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.728

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: This place is a probable branch point but likely benign (scored 1 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-55147029-C-T is Benign according to our data. Variant chr19-55147029-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55147029-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT1	NM_003283.6	c.33-8G>A		splice_region_variant, 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.33-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003283.6	ENSP00000467176

Frequencies

GnomAD3 genomes AF: 0.0457 AC: 6946 AN: 152108 Hom.: 236 Cov.: 32

Gnomad AFR AF: 0.0704

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0822

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.0600

Gnomad FIN AF: 0.0347

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0383

GnomAD3 exomes AF: 0.0482 AC: 11786 AN: 244394 Hom.: 467 AF XY: 0.0450 AC XY: 5947 AN XY: 132040

Gnomad AFR exome AF: 0.0735

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.0550

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0393

GnomAD4 exome AF: 0.0299 AC: 43608 AN: 1459458 Hom.: 1112 Cov.: 34 AF XY: 0.0299 AC XY: 21710 AN XY: 725772

Gnomad4 AFR exome AF: 0.0752

Gnomad4 AMR exome AF: 0.0997

Gnomad4 ASJ exome AF: 0.00955

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.0531

Gnomad4 FIN exome AF: 0.0301

Gnomad4 NFE exome AF: 0.0212

Gnomad4 OTH exome AF: 0.0323

GnomAD4 genome AF: 0.0457 AC: 6962 AN: 152226 Hom.: 237 Cov.: 32 AF XY: 0.0483 AC XY: 3595 AN XY: 74432

Gnomad4 AFR AF: 0.0705

Gnomad4 AMR AF: 0.0821

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.0597

Gnomad4 FIN AF: 0.0347

Gnomad4 NFE AF: 0.0212

Gnomad4 OTH AF: 0.0407

Alfa AF: 0.0231 Hom.: 39

Bravo AF: 0.0510

Asia WGS AF: 0.101 AC: 350 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 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.33-8G>A in intron 2 of TNNT1: This variant is not expected to have clinical si gnificance because it has been identified in 7.6% (333/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs76630067). -
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	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 5 Benign:2

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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Nemaline Myopathy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Familial restrictive cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.3
DANN	Benign	0.84
BranchPoint Hunter		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.053
dbscSNV1_RF	Benign	0.088
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: rs76630067; hg19: chr19-55658397;