chr19-55133074-G-A

Position:

• chr19-55133074-G-A

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.792-114C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 977,532 control chromosomes in the GnomAD database, including 35,289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4430 hom., cov: 31)
  • Exomes 𝑓: 0.26 (30859 hom.)
• Consequence: TNNT1 NM_003283.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.522

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=-0.8).
• BP6: Variant 19-55133074-G-A is Benign according to our data. Variant chr19-55133074-G-A is described in ClinVar as [Benign]. Clinvar id is 31858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT1	NM_003283.6	c.792-114C>T		intron_variant		ENST00000588981.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT1	ENST00000588981.6	c.792-114C>T		intron_variant		1	NM_003283.6

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35376 AN: 152030 Hom.: 4421 Cov.: 31

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.254

GnomAD4 exome AF: 0.264 AC: 217837 AN: 825384 Hom.: 30859 AF XY: 0.271 AC XY: 115869 AN XY: 427942

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.289

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.368

Gnomad4 SAS exome AF: 0.417

Gnomad4 FIN exome AF: 0.296

Gnomad4 NFE exome AF: 0.238

Gnomad4 OTH exome AF: 0.264

GnomAD4 genome AF: 0.233 AC: 35401 AN: 152148 Hom.: 4430 Cov.: 31 AF XY: 0.240 AC XY: 17838 AN XY: 74388

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.257

Gnomad4 ASJ AF: 0.299

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.429

Gnomad4 FIN AF: 0.295

Gnomad4 NFE AF: 0.243

Gnomad4 OTH AF: 0.255

Alfa AF: 0.248 Hom.: 2649

Bravo AF: 0.221

Asia WGS AF: 0.349 AC: 1214 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (TNNT1)	Mar 18, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.8
DANN	Benign	0.85

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: rs891186; hg19: chr19-55644442; COSMIC: COSV52574281; COSMIC: COSV52574281;