rs377417143
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001018005.2(TPM1):c.241-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
TPM1
NM_001018005.2 splice_polypyrimidine_tract, intron
NM_001018005.2 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00002314
2
Clinical Significance
Conservation
PhyloP100: 0.998
Genes affected
TPM1 (HGNC:12010): (tropomyosin 1) This gene is a member of the tropomyosin family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosin is composed of two alpha-helical chains arranged as a coiled-coil. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. The encoded protein is one type of alpha helical chain that forms the predominant tropomyosin of striated muscle, where it also functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. In smooth muscle and non-muscle cells, alternatively spliced transcript variants encoding a range of isoforms have been described. Mutations in this gene are associated with type 3 familial hypertrophic cardiomyopathy and dilated cardiomyopathy 1Y. [provided by RefSeq, Jun 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.68).
BP6
?
Variant 15-63056976-T-C is Benign according to our data. Variant chr15-63056976-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 43407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000171 (25/1461810) while in subpopulation EAS AF= 0.000479 (19/39698). AF 95% confidence interval is 0.000313. There are 0 homozygotes in gnomad4_exome. There are 9 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAdExome4 at 25 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPM1 | NM_001018005.2 | c.241-9T>C | splice_polypyrimidine_tract_variant, intron_variant | ENST00000403994.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPM1 | ENST00000403994.9 | c.241-9T>C | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_001018005.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251466Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135908
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GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461810Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727194
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74370
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ClinVar
Significance: Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cardiomyopathy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 01, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 08, 2019 | - - |
Hypertrophic cardiomyopathy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 27, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | - - |
not specified Benign:1
Likely benign, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 01, 2008 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at