rs1553248515

Positions:

• chr1-154170417-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_152263.4(TPM3):​c.758C>A​(p.Thr253Lys) variant causes a missense change. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM3 NM_152263.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.64

Genes affected

TPM3 (HGNC:12012): (tropomyosin 3) This gene encodes a member of the tropomyosin family of actin-binding proteins. Tropomyosins are dimers of coiled-coil proteins that provide stability to actin filaments and regulate access of other actin-binding proteins. Mutations in this gene result in autosomal dominant nemaline myopathy and other muscle disorders. This locus is involved in translocations with other loci, including anaplastic lymphoma receptor tyrosine kinase (ALK) and neurotrophic tyrosine kinase receptor type 1 (NTRK1), which result in the formation of fusion proteins that act as oncogenes. There are numerous pseudogenes for this gene on different chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a chain Tropomyosin alpha-3 chain (size 283) in uniprot entity TPM3_HUMAN there are 54 pathogenic changes around while only 2 benign (96%) in NM_152263.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TPM3. . Gene score misZ: 2.3546 (greater than the threshold 3.09). Trascript score misZ: 3.2484 (greater than threshold 3.09). The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. GenCC has associacion of the gene with congenital generalized hypercontractile muscle stiffness syndrome, intermediate nemaline myopathy, congenital myopathy 4B, autosomal recessive, cap myopathy, congenital fiber-type disproportion myopathy, congenital myopathy 4A, autosomal dominant, TPM3-related myopathy, childhood-onset nemaline myopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869
• PP5: Variant 1-154170417-G-T is Pathogenic according to our data. Variant chr1-154170417-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 462142.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM3	NM_152263.4	c.758C>A	p.Thr253Lys	missense_variant	8/10	ENST00000651641.1	NP_689476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM3	ENST00000651641.1	c.758C>A	p.Thr253Lys	missense_variant	8/10		NM_152263.4	ENSP00000498577.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myopathy with fiber type disproportion;C5829889:Congenital myopathy 4B, autosomal recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 24, 2017

For these reasons, this variant has been classified as Pathogenic. 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 disruptive, but these predictions have not been confirmed by published functional studies. This variant has been shown to arise de novo in an individual affected with congenital myopathy (PMID: 24692096). In addition, family studies have indicated that this variant was not present in the parents of an individual with congenital myopathy with dilated cardiomyopathy, which suggests that it was de novo in that affected individual (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with lysine at codon 253 of the TPM3 protein (p.Thr253Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.;.;D;.;.;.;.;.;.;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;D;D;D;D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	4.0	.;.;.;.;.;.;.;.;.;.;H
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.7	.;D;D;D;.;D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;D;D;D;.;D;D;D;D;D;D
Sift4G	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.95, 0.99	.;P;.;.;.;.;.;.;D;.;.
Vest4		0.81
MVP		0.91
MPC		2.4
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.80

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: rs1553248515; hg19: chr1-154142893;