1-154172972-G-A

Position:

• chr1-154172972-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_152263.4(TPM3):​c.502C>T​(p.Arg168Cys) variant causes a missense change involving the alteration of a 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R168G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM3 NM_152263.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:2
• Conservation: PhyloP100: 8.06

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a coiled_coil_region (size 284) in uniprot entity TPM3_HUMAN there are 32 pathogenic changes around while only 1 benign (97%) in NM_152263.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-154172972-G-C is described in Lovd as [Pathogenic].
• 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). GenCC has associacion of 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, 0.923
• PP5: Variant 1-154172972-G-A is Pathogenic according to our data. Variant chr1-154172972-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154172972-G-A is described in Lovd as [Pathogenic]. Variant chr1-154172972-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-154172972-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-154172972-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM3	NM_152263.4	c.502C>T	p.Arg168Cys	missense_variant	5/10	ENST00000651641.1	NP_689476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM3	ENST00000651641.1	c.502C>T	p.Arg168Cys	missense_variant	5/10		NM_152263.4	ENSP00000498577	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5 Other:1

not provided, no classification provided	literature only	TPM3 homepage - Leiden Muscular Dystrophy pages	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2022	Published functional studies demonstrate a decreased affinity for actin and reduced calcium-induced ATPase activation (Robaszkiewicz et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24692096, 24642510, 24456932, 20301436, 12467750, 32675003, 22749829, 19181092, 26307083, 18300303, 20554445, 24095155, 24507666, 19487656, 24239060, 20179953, 22172422, 23584160, 27363342, 29669168, 23886664, 22798622, 21357678, 19953533, 19553118, 17376686, 12601110, 12196661, 12163190, 10619715, 33646172, 33064836, 33652732, 33333461) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 21, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	TPM3: PM2, PM5, PM6, PS4:Moderate, PP3, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 29, 2016	- -

Congenital myopathy 4A, autosomal dominant Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics, Suma Genomics	-	A missense variant c.502C>T, p.(Arg168Cys) is observed in exon 5 of TPM3 in heterozygous state. This variant is not observed in the gnomAD database. This variant was reported earlier in the ClinVar database as pathogenic (ClinVar id. 12454). ACMG criteria: PS2, PS3, PM1, PM2_Supporting, PM6 and PP3 -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2016

- -

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

Jan 19, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 168 of the TPM3 protein (p.Arg168Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital myopathy, cap myopathy, nemaline myopathy, and congenital fiber type disproportion (PMID: 18300303, 19487656, 19953533, 20554445, 24095155, 24507666, 24642510, 24692096, 26307083, 27363342). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12454). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TPM3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TPM3 function (PMID: 22749829, 26307083). This variant disrupts the p.Arg168 amino acid residue in TPM3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12467750, 17376686, 19553118, 21357678, 22749829, 22798622, 23886664, 24507666, 24692096). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Nemaline myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Mar 01, 2024

PS3+PM1+PM2+PM5+PM6+PP2+PP3 -

Congenital myopathy with fiber type disproportion Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;.;D;.;.;.;.;.;.;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;T;D;T;.;T;D;D;T;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	.;.;.;.;.;.;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.5	.;D;D;D;.;D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;D;D;D;.;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.058, 0.010	.;B;.;.;.;.;.;.;B;.;.
Vest4		0.94
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121964854; hg19: chr1-154145448;