chr12-98533930-C-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_003276.2(TMPO):c.1673C>A(p.Thr558Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_003276.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMPO | NM_001032283.3 | c.565+2092C>A | intron_variant | Intron 3 of 8 | ENST00000556029.6 | NP_001027454.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152240Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251152Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135730
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461746Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727162
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152240Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74386
ClinVar
Submissions by phenotype
not specified Uncertain:1
The p.T558N variant (also known as c.1673C>A), located in coding exon 4 of the TMPO gene, results from a C to A substitution at nucleotide position 1673. The threonine at codon 558 is replaced by asparagine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Found in a 23-year-old female with unexplained postpartum sudden cardiac arrest, along with 5 other VUSs. p.Thr558Asn (c.1673C>A) in exon 4 of the TMPO gene (NM_003276.2; ENST00000266732.8) Chromosome location 12:98927708 C / A Based on the information reviewed below, we classify it as a Variant of Uncertain Significance (VUS). The TMPO gene currently has no well-established disease association; however there is preliminary evidence supporting a correlation with autosomal dominant dilated cardiomyopathy (DCM) (MedGen UID: 2880). This variant has not been reported in the literature in association with disease, according to the Invitae report. This is a conservative amino acid change, resulting in the replacement of a polar Threonine with a polar Asparagine. Threonine at this location is poorly conserved across the vertebrate species for which we have data. There are no Likely Pathogenic or Pathogenic variants currently listed in ClinVar within 10 amino acids to either side. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant was reported in 9 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Overall MAF: 0.004%. Specifically, the variant was observed in 6 Latino individuals (for minor allele frequency: 0.018%), 2 South Asians, and 1 "Other" ancestry. Of note: Whiffin et al (2017) proposed that variants with frequency greater than 0.008% are unlikely to be pathogenic for DCM. There is good coverage at this site. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. Our patient's ancestry is Latino. -
Loeys-Dietz syndrome 2 Uncertain:1
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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with TMPO-related disease. This variant is present in population databases (rs563175204, ExAC 0.009%). This sequence change replaces threonine with asparagine at codon 558 of the TMPO protein (p.Thr558Asn). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and asparagine. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at