rs121913036
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_001953.5(TYMP):āc.866A>Cā(p.Glu289Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000573 in 1,570,278 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 Pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E289K) has been classified as Uncertain significance.
Frequency
Consequence
NM_001953.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TYMP | NM_001953.5 | c.866A>C | p.Glu289Ala | missense_variant | 7/10 | ENST00000252029.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TYMP | ENST00000252029.8 | c.866A>C | p.Glu289Ala | missense_variant | 7/10 | 1 | NM_001953.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152116Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000530 AC: 9AN: 169894Hom.: 0 AF XY: 0.0000431 AC XY: 4AN XY: 92736
GnomAD4 exome AF: 0.0000585 AC: 83AN: 1418162Hom.: 0 Cov.: 36 AF XY: 0.0000513 AC XY: 36AN XY: 701966
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152116Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74306
ClinVar
Submissions by phenotype
Mitochondrial DNA depletion syndrome 1 Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 08, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 29, 1999 | - - |
Pathogenic, no assertion criteria provided | literature only | GeneReviews | Jan 14, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 22, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathophysiology and Transplantation, University of Milan | Jul 04, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 09, 2018 | The TYMP c.866A>C (p.Glu289Ala) missense variant has been reported in at least five studies and is found in a total of 12 individuals with mitochondrial neurogastrointestinal encophalopathy disease (MNGIE), including in at least four in a homozygous state and in eight in a compound heterozygous state (Nishino et al. 1999; Amiot et al. 2009; Bakker et al. 2010; Scarpelli et al. 2012; Finkenstedt et al. 2012). As of 2010, fewer than 70 individuals with features consistent with MNGIE had been reported, according to Gene Reviews (Shoffner, 2010). The p.Glu289Ala variant was absent from 63 control subjects and is reported at a frequency of 0.000604 in the Ashkenazi Jewish population of the Genome Aggregation Database. Assays of TYMP activity level in peripheral leukocytes from six affected individuals, including one homozygote and two compound heterozygotes with the p.Glu289Ala variant, and 19 controls revealed that probands had either no detectable TYMP activity or activity that was less than 5% of controls (Nishino et al. 1999). Based on the evidence, the p.Glu289Ala variant is classified as pathogenic for mitochondrial neurogastrointestinal encophalopathy disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 289 of the TYMP protein (p.Glu289Ala). This variant is present in population databases (rs121913036, gnomAD 0.06%). This missense change has been observed in individuals with TYMP-related conditions (PMID: 9924029, 10852545, 15781193, 20151198, 23341816). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16653). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TYMP protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 29, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19344718, 20151198, 10852545, 18787099, 21503690, 9924029, 24199812, 23430799, 23341816, 19748572, 19221117, 31267951, 33300680, 32849836) - |
Mitochondrial neurogastrointestinal encephalomyopathy Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at