1-154162364-CAAAAAAAAAAAAA-CAAAAAAAAAAAAAA

Variant names:

• chr1-154162364-C-CA
• rs58289686
• NM_152263.4:c.*5572dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_152263.4(TPM3):​c.*5572dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.35 (4909 hom., cov: 0)
• Consequence: TPM3 NM_152263.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.459
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

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.*5572dupT		3_prime_UTR	Exon 10 of 10	NP_689476.2	P06753-1
	TPM3	NM_001364682.1		c.*5572dupT		3_prime_UTR	Exon 10 of 10	NP_001351611.1	A0A2R2Y2Q3
	TPM3	NM_001364683.1		c.*5572dupT		3_prime_UTR	Exon 9 of 9	NP_001351612.1	P06753-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM3	ENST00000651641.1	MANE Select	c.*5572dupT		3_prime_UTR	Exon 10 of 10	ENSP00000498577.1	P06753-1
	TPM3	ENST00000330188.13	TSL:1	c.665-4644dupT		intron	N/A	ENSP00000339035.7	P06753-5
	TPM3	ENST00000368533.8	TSL:1	c.665-4644dupT		intron	N/A	ENSP00000357521.3	P06753-2

Frequencies

GnomAD3 genomes AF: 0.351 AC: 26261 AN: 74886 Hom.: 4911 Cov.: 0

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.376

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.352

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.384

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

GnomAD4 genome AF: 0.351 AC: 26246 AN: 74858 Hom.: 4909 Cov.: 0 AF XY: 0.345 AC XY: 11760 AN XY: 34122

African (AFR) AF: 0.260 AC: 5268 AN: 20298

American (AMR) AF: 0.484 AC: 2940 AN: 6072

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 1014 AN: 2112

East Asian (EAS) AF: 0.376 AC: 1175 AN: 3124

South Asian (SAS) AF: 0.369 AC: 763 AN: 2066

European-Finnish (FIN) AF: 0.279 AC: 621 AN: 2224

Middle Eastern (MID) AF: 0.357 AC: 45 AN: 126

European-Non Finnish (NFE) AF: 0.371 AC: 13885 AN: 37424

Other (OTH) AF: 0.380 AC: 356 AN: 936

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myopathy with fiber type disproportion (1)
-	1	-	Nemaline myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs58289686; hg19: chr1-154134840;