rs397516389
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2
The NM_001018005.2(TPM1):c.775G>A(p.Glu259Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E259Q) has been classified as Likely benign.
Frequency
Consequence
NM_001018005.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPM1 | NM_001018005.2 | c.775G>A | p.Glu259Lys | missense_variant, splice_region_variant | 9/10 | ENST00000403994.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPM1 | ENST00000403994.9 | c.775G>A | p.Glu259Lys | missense_variant, splice_region_variant | 9/10 | 1 | NM_001018005.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251014Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135686
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461666Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727138
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 24, 2021 | This sequence change replaces glutamic acid with lysine at codon 259 of the TPM1 protein (p.Glu259Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs397516389, ExAC 0.002%). This variant has not been reported in the literature in individuals with TPM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 43440). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 24, 2012 | The Glu259Lys variant in TPM1 has not been reported in the literature nor previo usly identified by our laboratory. Computational analyses (conservation, AlignGV GD, PolyPhen2, and SIFT) are limited/unavailable for this variant due to the pre sent of alternative transcript in TPM1. In summary, additional information is ne eded to fully assess the clinical significance of the Glu259Lys variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at