chr15-63064066-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP6
The NM_001018005.2(TPM1):c.775G>C(p.Glu259Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E259D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001018005.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPM1 | NM_001018005.2 | c.775G>C | p.Glu259Gln | 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>C | p.Glu259Gln | missense_variant, splice_region_variant | 9/10 | 1 | NM_001018005.2 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251014Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135686
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461666Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727138
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 12, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 259 of the TPM1 protein (p.Glu259Gln). This variant is present in population databases (rs397516389, gnomAD 0.009%). 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: 181653). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2012 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at