rs780372739

Positions:

• chr19-55137191-G-A
• chr19-55137191-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_003283.6(TNNT1):​c.523C>T​(p.Arg175Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TNNT1 NM_003283.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.20

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 Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT1	NM_003283.6	c.523C>T	p.Arg175Trp	missense_variant	11/14	ENST00000588981.6	NP_003274.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT1	ENST00000588981.6	c.523C>T	p.Arg175Trp	missense_variant	11/14	1	NM_003283.6	ENSP00000467176

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 251046 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460434 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726560

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2020	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 05, 2015	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2024

The c.523C>T (p.R175W) alteration is located in exon 11 (coding exon 10) of the TNNT1 gene. This alteration results from a C to T substitution at nucleotide position 523, causing the arginine (R) at amino acid position 175 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	.;.;.;D;D;.;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.76	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;.;.;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.3	.;.;M;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.6	.;D;D;.;.;.;.;.;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	.;D;D;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;.
Polyphen		1.0	D;D;D;.;D;.;.;.;.
Vest4		0.47
MutPred		0.61		.;.;Loss of disorder (P = 0.0069);.;Loss of disorder (P = 0.0069);.;.;.;Loss of disorder (P = 0.0069);
MVP		1.0
MPC		1.6
ClinPred		0.99	D
GERP RS		3.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.51
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs780372739; hg19: chr19-55648559; COSMIC: COSV52571360; COSMIC: COSV52571360;