15-63042831-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2
The NM_001018005.2(TPM1):āc.2T>Cā(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000055 ( 0 hom. )
Consequence
TPM1
NM_001018005.2 start_lost
NM_001018005.2 start_lost
Scores
8
7
1
Clinical Significance
Conservation
PhyloP100: 7.72
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 Uncertain_significance. Variant got 4 ACMG points.
PVS1
Start lost variant, no new inframe start found.
BS2
High AC in GnomAdExome4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TPM1 | NM_001018005.2 | c.2T>C | p.Met1? | start_lost | 1/10 | ENST00000403994.9 | NP_001018005.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TPM1 | ENST00000403994.9 | c.2T>C | p.Met1? | start_lost | 1/10 | 1 | NM_001018005.2 | ENSP00000385107 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248122Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134644
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GnomAD4 exome AF: 0.00000548 AC: 8AN: 1460586Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726688
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This variant results in the loss of the translation initiator methionine at codon 1 of the TPM1 gene. This variant is expected to disrupt translation initiation and result in an absent or truncated protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 24503780, 34486814). This variant has been identified in 1/248122 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function TPM1 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 25, 2022 | This sequence change affects the initiator methionine of the TPM1 mRNA. The next in-frame methionine is located at codon 8. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TPM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1374193). 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. - |
Hypertrophic cardiomyopathy 3;C2678476:Dilated cardiomyopathy 1Y Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 01, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;D;.;D;T;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D;D;D
PROVEAN
Uncertain
D;D;.;D;D;D;D;D;D;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;D;D;D;D;D;D;.;.
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;.;.
Polyphen
1.0, 1.0
.;.;.;.;D;D;.;.;.;D;.
Vest4
MutPred
Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at