rs34313388

Positions:

• chr19-55141216-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_003283.6(TNNT1):​c.279A>G​(p.Glu93=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000487 in 1,614,226 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: TNNT1 NM_003283.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2 O:1
• Conservation: PhyloP100: -0.911

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-55141216-T-C is Benign according to our data. Variant chr19-55141216-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 31856.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=1, not_provided=1}.
• BP7: Synonymous conserved (PhyloP=-0.911 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT1	NM_003283.6	c.279A>G	p.Glu93=	synonymous_variant	8/14	ENST00000588981.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT1	ENST00000588981.6	c.279A>G	p.Glu93=	synonymous_variant	8/14	1	NM_003283.6

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 416 AN: 152240 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00950

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000704 AC: 177 AN: 251430 Hom.: 2 AF XY: 0.000471 AC XY: 64 AN XY: 135912

Gnomad AFR exome AF: 0.00929

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000252 AC: 368 AN: 1461868 Hom.: 1 Cov.: 31 AF XY: 0.000206 AC XY: 150 AN XY: 727234

Gnomad4 AFR exome AF: 0.00860

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.00274 AC: 418 AN: 152358 Hom.: 5 Cov.: 32 AF XY: 0.00231 AC XY: 172 AN XY: 74508

Gnomad4 AFR AF: 0.00955

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.00303

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 5 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2021	- -
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	-0.70
CADD	Benign	9.1
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

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: rs34313388; hg19: chr19-55652584;