NM_003283.6:c.817G>C

Variant names:

• chr19-55132935-C-G
• rs774212109
• NM_003283.6:c.817G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003283.6(TNNT1):​c.817G>C​(p.Val273Leu) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V273I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TNNT1 NM_003283.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 0 publications found

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]

TNNT1 Gene-Disease associations (from GenCC):

• nemaline myopathy 5

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nemaline myopathy 5B, autosomal recessive, childhood-onset

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• nemaline myopathy

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, ClinGen
• nemaline myopathy 5C, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0950889).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003283.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT1	NM_003283.6	MANE Select	c.817G>C	p.Val273Leu	missense	Exon 14 of 14	NP_003274.3
	TNNT1	NM_001126132.3		c.769G>C	p.Val257Leu	missense	Exon 14 of 14	NP_001119604.1	P13805-3
	TNNT1	NM_001126133.3		c.736G>C	p.Val246Leu	missense	Exon 13 of 13	NP_001119605.1	P13805-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT1	ENST00000588981.6	TSL:1 MANE Select	c.817G>C	p.Val273Leu	missense	Exon 14 of 14	ENSP00000467176.1	P13805-1
	TNNT1	ENST00000291901.12	TSL:1	c.769G>C	p.Val257Leu	missense	Exon 14 of 14	ENSP00000291901.8	P13805-3
	TNNT1	ENST00000356783.9	TSL:1	c.736G>C	p.Val246Leu	missense	Exon 13 of 13	ENSP00000349233.4	P13805-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.095	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.4	L
PhyloP100		1.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.37
Sift	Benign	0.042	D
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.15
MutPred		0.21		Loss of methylation at K278 (P = 0.0491)
MVP		0.87
MPC		0.60
ClinPred		0.88	D
GERP RS		1.7
Varity_R		0.20
gMVP		0.29
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs774212109; hg19: chr19-55644303;