1-154176194-G-T

Variant names:

• chr1-154176194-G-T
• rs121964853
• NM_152263.4:c.298C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001278191.2(TPM3):​c.-84C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-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 (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TPM3 NM_001278191.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:2
• Conservation: PhyloP100: 3.27
• Publications: 11 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 1-154176194-G-T is Pathogenic according to our data. Variant chr1-154176194-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12452.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278191.2. 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.298C>A	p.Leu100Met	missense	Exon 3 of 10	NP_689476.2	P06753-1
	TPM3	NM_001278191.2		c.-84C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	NP_001265120.1	P06753-7
	TPM3	NM_001364679.2		c.298C>A	p.Leu100Met	missense	Exon 3 of 9	NP_001351608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM3	ENST00000651641.1	MANE Select	c.298C>A	p.Leu100Met	missense	Exon 3 of 10	ENSP00000498577.1	P06753-1
	TPM3	ENST00000368530.7	TSL:1	c.298C>A	p.Leu100Met	missense	Exon 3 of 10	ENSP00000357516.3	A0A2R2Y2Q3
	TPM3	ENST00000330188.13	TSL:1	c.187C>A	p.Leu63Met	missense	Exon 2 of 8	ENSP00000339035.7	P06753-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital myopathy 4A, autosomal dominant (1)
-	-	-	Congenital myopathy with fiber type disproportion (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
PhyloP100		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.88
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

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

Other links and lift over

dbSNP: rs121964853; hg19: chr1-154148670;