NM_152263.4:c.857_*1delAAT

Variant names:

• chr1-154167934-TAAT-TA
• NM_152263.4:c.858_*1delAT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_152263.4(TPM3):​c.858_*1delAT​(p.Ter286fs) variant causes a frameshift, stop lost change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM3 NM_152263.4 frameshift, stop_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.66
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• congenital myopathy 4A, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• TPM3-related myopathy

  Inheritance: SD, AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital myopathy 4B, autosomal recessive

  Inheritance: SD, AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital fiber-type disproportion myopathy

  Inheritance: SD, AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• cap myopathy

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital generalized hypercontractile muscle stiffness syndrome

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152263.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM3	NM_152263.4	MANE Select	c.858_*1delAT	p.Ter286fs	frameshift stop_lost	Exon 10 of 10	NP_689476.2	P06753-1
	TPM3	NM_152263.4	MANE Select	c.858_*1delAT		3_prime_UTR	Exon 10 of 10	NP_689476.2	P06753-1
	TPM3	NM_001364682.1		c.858_*1delAT	p.Ter286fs	frameshift stop_lost	Exon 10 of 10	NP_001351611.1	A0A2R2Y2Q3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM3	ENST00000651641.1	MANE Select	c.858_*1delAT	p.Ter286fs	frameshift stop_lost	Exon 10 of 10	ENSP00000498577.1	P06753-1
	TPM3	ENST00000368530.7	TSL:1	c.858_*1delAT	p.Ter286fs	frameshift stop_lost	Exon 10 of 10	ENSP00000357516.3	A0A2R2Y2Q3
	TPM3	ENST00000651641.1	MANE Select	c.858_*1delAT		3_prime_UTR	Exon 10 of 10	ENSP00000498577.1	P06753-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-154140410;