1-154191169-ATCTC-ATC

Variant names:

• chr1-154191169-ATC-A
• rs146969764
• NM_152263.4:c.243+15_243+16delGA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_152263.4(TPM3):​c.243+15_243+16delGA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00428 in 1,613,494 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (16 hom.)
• Consequence: TPM3 NM_152263.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.333
• Publications: 0 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 -9 ACMG points.

• BP6: Variant 1-154191169-ATC-A is Benign according to our data. Variant chr1-154191169-ATC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262623.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00403 (612/151682) while in subpopulation AMR AF = 0.00742 (113/15230). AF 95% confidence interval is 0.00631. There are 2 homozygotes in GnomAd4. There are 314 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 SD,AD,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.243+15_243+16delGA		intron	N/A	NP_689476.2	P06753-1
	TPM3	NM_001364679.2		c.243+15_243+16delGA		intron	N/A	NP_001351608.1
	TPM3	NM_001364680.2		c.243+15_243+16delGA		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+15_243+16delGA		intron	N/A	ENSP00000498577.1	P06753-1
	TPM3	ENST00000368530.7	TSL:1	c.243+15_243+16delGA		intron	N/A	ENSP00000357516.3	A0A2R2Y2Q3
	TPM3	ENST00000960967.1		c.243+15_243+16delGA		intron	N/A	ENSP00000631026.1

Frequencies

GnomAD3 genomes AF: 0.00404 AC: 612 AN: 151564 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000802

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00743

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00708

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00563

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00376 AC: 942 AN: 250324 AF XY: 0.00377

Gnomad AFR exome AF: 0.000836

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00527

Gnomad NFE exome AF: 0.00599

Gnomad OTH exome AF: 0.00362

GnomAD4 exome AF: 0.00430 AC: 6290 AN: 1461812 Hom.: 16 AF XY: 0.00417 AC XY: 3034 AN XY: 727214

African (AFR) AF: 0.000896 AC: 30 AN: 33474

American (AMR) AF: 0.00282 AC: 126 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86252

European-Finnish (FIN) AF: 0.00528 AC: 282 AN: 53372

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00503 AC: 5597 AN: 1111992

Other (OTH) AF: 0.00381 AC: 230 AN: 60396

GnomAD4 genome AF: 0.00403 AC: 612 AN: 151682 Hom.: 2 Cov.: 32 AF XY: 0.00423 AC XY: 314 AN XY: 74164

African (AFR) AF: 0.000799 AC: 33 AN: 41284

American (AMR) AF: 0.00742 AC: 113 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00708 AC: 75 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00563 AC: 382 AN: 67856

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00223 Hom.: 0

Bravo AF: 0.00314

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myopathy with fiber type disproportion (1)
-	-	1	Congenital myopathy with fiber type disproportion;C5829889:Congenital myopathy 4B, autosomal recessive (1)
-	1	-	Nemaline myopathy (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism

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: rs146969764; hg19: chr1-154163645;