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. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 262623.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=2}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM3	NM_152263.4	c.243+15_243+16delGA		intron_variant	Intron 2 of 9	ENST00000651641.1	NP_689476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM3	ENST00000651641.1	c.243+15_243+16delGA		intron_variant	Intron 2 of 9		NM_152263.4	ENSP00000498577.1

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

GnomAD3 exomes AF: 0.00376 AC: 942 AN: 250324 Hom.: 4 AF XY: 0.00377 AC XY: 512 AN XY: 135740

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 SAS exome AF: 0.0000980

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

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00528

Gnomad4 NFE exome AF: 0.00503

Gnomad4 OTH exome AF: 0.00381

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

Gnomad4 AFR AF: 0.000799

Gnomad4 AMR AF: 0.00742

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00708

Gnomad4 NFE AF: 0.00563

Gnomad4 OTH AF: 0.00379

Bravo AF: 0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myopathy with fiber type disproportion Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myopathy with fiber type disproportion;C5829889:Congenital myopathy 4B, autosomal recessive Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 05, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs146969764; hg19: chr1-154163645;