chr1-154162364-C-CAA

Variant names:

• chr1-154162364-C-CAA
• rs58289686
• NM_152263.4:c.*5571_*5572dupTT

Variant summary

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

The NM_152263.4(TPM3):​c.*5571_*5572dupTT 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 0.019 (38 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 eas. GnomAd4 allele frequency = 0.0189 (1413/74740) while in subpopulation EAS AF = 0.0313 (98/3132). AF 95% confidence interval is 0.0263. There are 38 homozygotes in GnomAd4. There are 622 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 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.*5571_*5572dupTT		3_prime_UTR	Exon 10 of 10	NP_689476.2	P06753-1
	TPM3	NM_001364682.1		c.*5571_*5572dupTT		3_prime_UTR	Exon 10 of 10	NP_001351611.1	A0A2R2Y2Q3
	TPM3	NM_001364683.1		c.*5571_*5572dupTT		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.*5571_*5572dupTT		3_prime_UTR	Exon 10 of 10	ENSP00000498577.1	P06753-1
	TPM3	ENST00000330188.13	TSL:1	c.665-4645_665-4644dupTT		intron	N/A	ENSP00000339035.7	P06753-5
	TPM3	ENST00000368533.8	TSL:1	c.665-4645_665-4644dupTT		intron	N/A	ENSP00000357521.3	P06753-2

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 1415 AN: 74766 Hom.: 38 Cov.: 0

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00422

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.0315

Gnomad SAS AF: 0.00481

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0268

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

GnomAD4 genome AF: 0.0189 AC: 1413 AN: 74740 Hom.: 38 Cov.: 0 AF XY: 0.0182 AC XY: 622 AN XY: 34098

African (AFR) AF: 0.0159 AC: 323 AN: 20292

American (AMR) AF: 0.0112 AC: 68 AN: 6068

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 31 AN: 2104

East Asian (EAS) AF: 0.0313 AC: 98 AN: 3132

South Asian (SAS) AF: 0.00484 AC: 10 AN: 2064

European-Finnish (FIN) AF: 0.0184 AC: 41 AN: 2232

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

European-Non Finnish (NFE) AF: 0.0217 AC: 810 AN: 37308

Other (OTH) AF: 0.0267 AC: 25 AN: 938

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;