19-55137191-G-C

Position:

• chr19-55137191-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003283.6(TNNT1):​c.523C>G​(p.Arg175Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R175W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TNNT1 NM_003283.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT1	NM_003283.6	c.523C>G	p.Arg175Gly	missense_variant	11/14	ENST00000588981.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT1	ENST00000588981.6	c.523C>G	p.Arg175Gly	missense_variant	11/14	1	NM_003283.6

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2020

This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 175 of the TNNT1 protein (p.Arg175Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant has not been reported in the literature in individuals with TNNT1-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	.;.;.;D;D;.;.;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D;.;.;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.3	.;.;L;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.6	.;D;D;.;.;.;.;.;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	.;D;D;.;.;.;.;.;.
Sift4G	Benign	0.068	T;T;T;T;T;T;T;T;.
Polyphen		0.95	P;P;D;.;D;.;.;.;.
Vest4		0.48
MutPred		0.64		.;.;Loss of methylation at K174 (P = 0.0492);.;Loss of methylation at K174 (P = 0.0492);.;.;.;Loss of methylation at K174 (P = 0.0492);
MVP		0.97
MPC		0.81
ClinPred		0.95	D
GERP RS		3.1
Varity_R		0.53
gMVP		0.45

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: rs780372739; hg19: chr19-55648559;