1-154167941-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PM2PP3_Strong
The NM_152263.4(TPM3):c.855-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000041 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
TPM3
NM_152263.4 splice_acceptor
NM_152263.4 splice_acceptor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.62
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease,
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPM3 | NM_152263.4 | c.855-1G>A | splice_acceptor_variant | ENST00000651641.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPM3 | ENST00000651641.1 | c.855-1G>A | splice_acceptor_variant | NM_152263.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000202 AC: 5AN: 247088Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134284
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461798Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727206
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1Other:1
not provided, no classification provided | literature only | TPM3 homepage - Leiden Muscular Dystrophy pages | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 25, 2022 | - - |
Congenital myopathy 4B, autosomal recessive Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 27, 2002 | - - |
Congenital myopathy with fiber type disproportion;C5829889:Congenital myopathy 4B, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 06, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 12196661). ClinVar contains an entry for this variant (Variation ID: 12448). This variant has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 12196661). This variant is present in population databases (rs113605263, gnomAD 0.01%). This sequence change falls in intron 9 of the TPM3 gene. It does not directly change the encoded amino acid sequence of the TPM3 protein. It affects a nucleotide within the consensus splice site. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at