rs104894128

Variant names:

• chr9-35685486-T-G
• rs104894128
• NM_003289.4:c.440A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_003289.4(TPM2):​c.440A>C​(p.Gln147Pro) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM2 NM_003289.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 8.01
• Publications: 12 publications found

Genes affected

TPM2 (HGNC:12011): (tropomyosin 2) This gene encodes beta-tropomyosin, a member of the actin filament binding protein family, and mainly expressed in slow, type 1 muscle fibers. Mutations in this gene can alter the expression of other sarcomeric tropomyosin proteins, and cause cap disease, nemaline myopathy and distal arthrogryposis syndromes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

TPM2 Gene-Disease associations (from GenCC):

• TPM2-related myopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arthrogryposis, distal, type 1A

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• congenital myopathy 23

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• cap myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• digitotalar dysmorphism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sheldon-hall syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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, 6 uncertain in NM_003289.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TPM2 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 1 curated benign missense variants. Gene score misZ: 2.1346 (below the threshold of 3.09). Trascript score misZ: 3.2995 (above the threshold of 3.09). GenCC associations: The gene is linked to cap myopathy, arthrogryposis, distal, type 1A, typical nemaline myopathy, TPM2-related myopathy, Sheldon-hall syndrome, congenital fiber-type disproportion myopathy, congenital myopathy, congenital myopathy 23, digitotalar dysmorphism, childhood-onset nemaline myopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_003289.4	c.440A>C	p.Gln147Pro	missense_variant	Exon 4 of 9	ENST00000645482.3	NP_003280.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3	c.440A>C	p.Gln147Pro	missense_variant	Exon 4 of 9		NM_003289.4	ENSP00000496494.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myopathy 23 Pathogenic:1

Feb 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Arthrogryposis, distal, type 1A Uncertain:1

Jun 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 147 of the TPM2 protein (p.Gln147Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with nemaline myopathy (PMID: 11738357). ClinVar contains an entry for this variant (Variation ID: 12461). 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 TPM2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TPM2 function (PMID: 22084935, 26708479, 30545627). 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. -

not provided Other:1

-

TPM2 homepage - Leiden Muscular Dystrophy pages

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	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	.;D;.;D;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	.;D;D;.;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.4	H;.;H;H;H;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.5	D;D;D;.;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;D;.;D;.
Sift4G	Uncertain	0.0030	D;D;D;.;D;.
Polyphen		0.99	D;.;D;D;D;P
Vest4		0.87
MutPred		0.70		Gain of methylation at K149 (P = 0.1048);Gain of methylation at K149 (P = 0.1048);Gain of methylation at K149 (P = 0.1048);Gain of methylation at K149 (P = 0.1048);Gain of methylation at K149 (P = 0.1048);Gain of methylation at K149 (P = 0.1048);
MVP		0.97
MPC		2.3
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		0.018	Neutral
Varity_R		0.86
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894128; hg19: chr9-35685483;