rs199474711

Variant names:

• chr1-154192008-G-A
• rs199474711
• NM_152263.4:c.11C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_152263.4(TPM3):​c.11C>T​(p.Ala4Val) 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM3 NM_152263.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:2
• Conservation: PhyloP100: 10.0

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 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_152263.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM3	NM_152263.4	c.11C>T	p.Ala4Val	missense_variant	Exon 1 of 10	ENST00000651641.1	NP_689476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM3	ENST00000651641.1	c.11C>T	p.Ala4Val	missense_variant	Exon 1 of 10		NM_152263.4	ENSP00000498577.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Other:1

-

TPM3 homepage - Leiden Muscular Dystrophy pages

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 24, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in multiple affected individuals in a family with congenital fiber type disproportion in published literature (Lawlor et al., 2010); This variant is associated with the following publications: (PMID: 19953533) -

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

Sep 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 42113). This missense change has been observed in individuals with clinical features of congenital myopathy (PMID: 19953533; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4 of the TPM3 protein (p.Ala4Val). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects TPM3 function (PMID: 30768849). -

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	0.81
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	.;M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N;N;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.042	D;T;.
Vest4		0.87
MVP		0.97
MPC		2.3
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.42

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: rs199474711; hg19: chr1-154164484; COSMIC: COSV99665945; COSMIC: COSV99665945;