NM_152263.4:c.243+5275A>G

Variant names:

• chr1-154185911-T-C
• rs4845605
• NM_152263.4:c.243+5275A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152263.4(TPM3):​c.243+5275A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 150,804 control chromosomes in the GnomAD database, including 31,492 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.63 (31492 hom., cov: 29)
• Consequence: TPM3 NM_152263.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.371
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.862 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.243+5275A>G		intron	N/A	NP_689476.2	P06753-1
	TPM3	NM_001364679.2		c.243+5275A>G		intron	N/A	NP_001351608.1
	TPM3	NM_001364680.2		c.243+5275A>G		intron	N/A	NP_001351609.1	J3KN67

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM3	ENST00000651641.1	MANE Select	c.243+5275A>G		intron	N/A	ENSP00000498577.1	P06753-1
	TPM3	ENST00000368530.7	TSL:1	c.243+5275A>G		intron	N/A	ENSP00000357516.3	A0A2R2Y2Q3
	TPM3	ENST00000960967.1		c.243+5275A>G		intron	N/A	ENSP00000631026.1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 95237 AN: 150686 Hom.: 31455 Cov.: 29

Gnomad AFR AF: 0.766

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.691

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.882

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.627

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

GnomAD4 genome AF: 0.632 AC: 95327 AN: 150804 Hom.: 31492 Cov.: 29 AF XY: 0.636 AC XY: 46895 AN XY: 73688

African (AFR) AF: 0.766 AC: 30947 AN: 40390

American (AMR) AF: 0.691 AC: 10526 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1913 AN: 3466

East Asian (EAS) AF: 0.883 AC: 4572 AN: 5178

South Asian (SAS) AF: 0.679 AC: 3267 AN: 4810

European-Finnish (FIN) AF: 0.584 AC: 6146 AN: 10526

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.531 AC: 36050 AN: 67908

Other (OTH) AF: 0.624 AC: 1306 AN: 2092

Alfa AF: 0.568 Hom.: 48836

Bravo AF: 0.650

Asia WGS AF: 0.769 AC: 2672 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.40
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4845605; hg19: chr1-154158387;