rs121964852

chr1-154172971-C-T

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.503G>A(p.Arg168His) 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. 11/19 in silico tools predict a damaging 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. R168C) 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:8 O:2
• Conservation: PhyloP100: 7.85

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 chain Tropomyosin alpha-3 chain (size 283) in uniprot entity TPM3_HUMAN there are 53 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-A is described in ClinVar as [Pathogenic]. Clinvar id is 12454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, TPM3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 1-154172971-C-T is Pathogenic according to our data. Variant chr1-154172971-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-154172971-C-T is described in Lovd as [Pathogenic]. Variant chr1-154172971-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-154172971-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM3	NM_152263.4	c.503G>A	p.Arg168His	missense_variant	5/10	ENST00000651641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM3	ENST00000651641.1	c.503G>A	p.Arg168His	missense_variant	5/10		NM_152263.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 22, 2021	PP1, PP3, PM2, PM6, PS3, PS4_moderate -
not provided, no classification provided	literature only	TPM3 homepage - Leiden Muscular Dystrophy pages	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2021	Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12467750, 22749829, 23886664, 22798622, 24692096, 17376686, 26307083, 19553118, 18300303, 19953533, 20951040, 32140910, 33333461, 31270709) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 29, 2018	Not found in the total gnomAD dataset, and the data is high quality (0/277230 chr). Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease, and data include both affected and unaffected members from multiple families. 3 de novo cases without parental identity confirmed. 1 de novo case with parental identity confirmed. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	TPM3: PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -

Congenital myopathy 4B, autosomal recessive Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 12, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 168 of the TPM3 protein (p.Arg168His). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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: 24095155, 24692096). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TPM3 function (PMID: 21357678, 22749829, 22798622, 23886664). 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 not expected to disrupt TPM3 protein function. ClinVar contains an entry for this variant (Variation ID: 12450). This variant is also known as p.Arg167His. This missense change has been observed in individual(s) with autosomal dominant nemaline myopathy, cap myopathy, congenital myopathy, and congenital fiber type disproportion (PMID: 12467750, 17376686, 19553118, 21357678, 24507666, 24692096). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. -

Congenital myopathy 4A, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2009

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Apr 26, 2021

PP5_very strong;PS3_strong;PM2_supporting;PM5_moderate;PP2_supporting;PP3_supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;.;.;D;.;.;.;.;.;.;D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.62	T;T;T;T;.;T;T;T;T;T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.86	D
Sift4G	Uncertain	0.050	T;D;D;D;T;D;D;T;D;D;D
Polyphen		0.011, 0.0040	.;B;.;.;.;.;.;.;B;.;.
Vest4		0.93
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.53

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: rs121964852; hg19: chr1-154145447;