19-55133074-G-A

Variant names:

• chr19-55133074-G-A
• rs891186
• NM_003283.6:c.792-114C>T

Variant summary

Our verdict is Benign. The variant received -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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TNNT1	NM_003283.6	c.792-114C>T		intron_variant	Intron 13 of 13	ENST00000588981.6	NP_003274.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT1	ENST00000588981.6	c.792-114C>T		intron_variant	Intron 13 of 13	1	NM_003283.6	ENSP00000467176.1

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 AC: 2929 AN: 20460

Gnomad4 AMR exome AF: 0.289 AC: 9911 AN: 34278

Gnomad4 ASJ exome AF: 0.298 AC: 6421 AN: 21556

Gnomad4 EAS exome AF: 0.368 AC: 12214 AN: 33216

Gnomad4 SAS exome AF: 0.417 AC: 28130 AN: 67494

Gnomad4 FIN exome AF: 0.296 AC: 12124 AN: 40972

Gnomad4 NFE exome AF: 0.238 AC: 134410 AN: 563758

Gnomad4 Remaining exome AF: 0.264 AC: 10366 AN: 39280

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 AC: 0.144667 AN: 0.144667

Gnomad4 AMR AF: 0.257 AC: 0.256776 AN: 0.256776

Gnomad4 ASJ AF: 0.299 AC: 0.298559 AN: 0.298559

Gnomad4 EAS AF: 0.361 AC: 0.361401 AN: 0.361401

Gnomad4 SAS AF: 0.429 AC: 0.428779 AN: 0.428779

Gnomad4 FIN AF: 0.295 AC: 0.295046 AN: 0.295046

Gnomad4 NFE AF: 0.243 AC: 0.242978 AN: 0.242978

Gnomad4 OTH AF: 0.255 AC: 0.254976 AN: 0.254976

Alfa AF: 0.247 Hom.: 2897

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 18, 2012

Leiden Muscular Dystrophy (TNNT1)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
Mutation Taster		=100/0	polymorphism (auto)

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;