NM_152263.4:c.502C>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_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 Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

TPM3
NM_152263.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:2

Conservation

PhyloP100: 8.06

Variant links:

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]

TPM3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-154172972-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the TPM3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 2.3546 (below the threshold of 3.09). Trascript score misZ: 3.2484 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
TPM3	NM_152263.4 link	c.502C>T	p.Arg168Cys	missense_variant	Exon 5 of 10	ENST00000651641.1	NP_689476.2	P06753-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM3	ENST00000651641.1 link	c.502C>T	p.Arg168Cys	missense_variant	Exon 5 of 10		NM_152263.4	ENSP00000498577.1		P06753-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Other:1

TPM3 homepage - Leiden Muscular Dystrophy pages

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 11, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Nov 29, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 21, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TPM3: PM2, PM5, PM6, PS4:Moderate, PP3, PP4, PS3:Supporting -

Congenital myopathy 4A, autosomal dominant

Pathogenic:2

Dec 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 07, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Jul 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 01, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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

Congenital myopathy with fiber type disproportion

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

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

LIST_S2

Benign

0.85

D;T;D;T;.;T;D;D;T;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

.;.;.;.;.;.;.;.;.;.;H

PrimateAI

Pathogenic

0.89

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over