chr15-63071092-A-G
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001365778.1(TPM1):āc.901A>Gā(p.Lys301Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 1,614,132 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00051 ( 0 hom., cov: 32)
Exomes š: 0.00050 ( 0 hom. )
Consequence
TPM1
NM_001365778.1 missense, splice_region
NM_001365778.1 missense, splice_region
Scores
2
3
12
Clinical Significance
Conservation
PhyloP100: 9.11
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 -12 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TPM1. . Gene score misZ: 2.8677 (greater than the threshold 3.09). Trascript score misZ: 3.593 (greater than threshold 3.09). The gene has 42 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. GenCC has associacion of the gene with dilated cardiomyopathy, left ventricular noncompaction, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 3, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1Y.
BP4
Computational evidence support a benign effect (MetaRNN=0.008403361).
BP6
Variant 15-63071092-A-G is Benign according to our data. Variant chr15-63071092-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43687.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=1}. Variant chr15-63071092-A-G is described in Lovd as [Benign]. Variant chr15-63071092-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0005 (731/1461770) while in subpopulation NFE AF= 0.000341 (379/1111954). AF 95% confidence interval is 0.000312. There are 0 homozygotes in gnomad4_exome. There are 355 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 77 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TPM1 | NM_001365778.1 | c.901A>G | p.Lys301Glu | missense_variant, splice_region_variant | 10/10 | NP_001352707.1 | ||
TPM1 | NM_001407326.1 | c.854A>G | p.Glu285Gly | missense_variant, splice_region_variant | 10/10 | NP_001394255.1 | ||
TPM1 | NM_001018004.2 | c.775A>G | p.Lys259Glu | missense_variant, splice_region_variant | 9/9 | NP_001018004.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TPM1 | ENST00000267996.11 | c.775A>G | p.Lys259Glu | missense_variant, splice_region_variant | 9/9 | 1 | ENSP00000267996.7 | |||
TPM1 | ENST00000358278.7 | c.775A>G | p.Lys259Glu | missense_variant, splice_region_variant | 9/9 | 1 | ENSP00000351022.3 | |||
TPM1 | ENST00000404484.9 | c.667A>G | p.Lys223Glu | missense_variant, splice_region_variant | 8/8 | 1 | ENSP00000384315.4 |
Frequencies
GnomAD3 genomes AF: 0.000506 AC: 77AN: 152244Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000815 AC: 203AN: 248946Hom.: 0 AF XY: 0.000757 AC XY: 102AN XY: 134754
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GnomAD4 exome AF: 0.000500 AC: 731AN: 1461770Hom.: 0 Cov.: 33 AF XY: 0.000488 AC XY: 355AN XY: 727180
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GnomAD4 genome AF: 0.000505 AC: 77AN: 152362Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44AN XY: 74506
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:2
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 21, 2012 | Lys259Glu in exon 10 of TPM1: This variant is not expected to have clinical sign ificance because it has been identified in 1.6% (3/186) of Finnish chromosomes b y the 1000 genomes project (rs144045691). At this frequency it is unlikely disea se causing though a modifying role cannot be excluded. Lys259Glu in exon 10 of TPM1 (rs144045691; allele frequency = 1.6%, 3/186) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jul 04, 2017 | - - |
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 25, 2019 | This variant is associated with the following publications: (PMID: 23785128, 28798025, 30847666) - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Nov 19, 2013 | - - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 18, 2018 | - - |
TPM1-related disorder Benign:1
Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 19, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
.;T;.;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;D;D;D;D;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T
Polyphen
0.0
.;B;.;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at