1-154162364-CAAAAAAAAAAAAA-CAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_152263.4(TPM3):​c.*5572delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.014 (14 hom., cov: 0)
• Consequence: TPM3 NM_152263.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0138 (1039/75066) while in subpopulation AFR AF = 0.0377 (767/20330). AF 95% confidence interval is 0.0355. There are 14 homozygotes in GnomAd4. There are 499 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AD,SD,AR gene

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.*5572delT		3_prime_UTR	Exon 10 of 10	NP_689476.2	P06753-1
	TPM3	NM_001364682.1		c.*5572delT		3_prime_UTR	Exon 10 of 10	NP_001351611.1	A0A2R2Y2Q3
	TPM3	NM_001364683.1		c.*5572delT		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.*5572delT		3_prime_UTR	Exon 10 of 10	ENSP00000498577.1	P06753-1
	TPM3	ENST00000330188.13	TSL:1	c.665-4644delT		intron	N/A	ENSP00000339035.7	P06753-5
	TPM3	ENST00000368533.8	TSL:1	c.665-4644delT		intron	N/A	ENSP00000357521.3	P06753-2

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 1039 AN: 75094 Hom.: 14 Cov.: 0

Gnomad AFR AF: 0.0377

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00559

Gnomad ASJ AF: 0.00473

Gnomad EAS AF: 0.0118

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0486

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.00857

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

GnomAD4 genome AF: 0.0138 AC: 1039 AN: 75066 Hom.: 14 Cov.: 0 AF XY: 0.0146 AC XY: 499 AN XY: 34218

African (AFR) AF: 0.0377 AC: 767 AN: 20330

American (AMR) AF: 0.00559 AC: 34 AN: 6084

Ashkenazi Jewish (ASJ) AF: 0.00473 AC: 10 AN: 2116

East Asian (EAS) AF: 0.0118 AC: 37 AN: 3132

South Asian (SAS) AF: 0.0179 AC: 37 AN: 2066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2234

Middle Eastern (MID) AF: 0.0391 AC: 5 AN: 128

European-Non Finnish (NFE) AF: 0.00375 AC: 141 AN: 37556

Other (OTH) AF: 0.00851 AC: 8 AN: 940

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

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;