rs142073519
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4
The NM_006567.5(FARS2):āc.971A>Gā(p.Tyr324Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000954 in 1,614,040 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). Synonymous variant affecting the same amino acid position (i.e. Y324Y) has been classified as Likely benign.
Frequency
Consequence
NM_006567.5 missense
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 |
---|---|---|---|---|---|---|---|
FARS2 | NM_006567.5 | c.971A>G | p.Tyr324Cys | missense_variant | 5/7 | ENST00000274680.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FARS2 | ENST00000274680.9 | c.971A>G | p.Tyr324Cys | missense_variant | 5/7 | 1 | NM_006567.5 | P1 | |
FARS2 | ENST00000324331.10 | c.971A>G | p.Tyr324Cys | missense_variant | 5/7 | 1 | P1 | ||
FARS2 | ENST00000648580.1 | c.971A>G | p.Tyr324Cys | missense_variant, NMD_transcript_variant | 5/9 |
Frequencies
GnomAD3 genomes ? AF: 0.000467 AC: 71AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000163 AC: 41AN: 251280Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135810
GnomAD4 exome AF: 0.0000568 AC: 83AN: 1461760Hom.: 0 Cov.: 31 AF XY: 0.0000481 AC XY: 35AN XY: 727186
GnomAD4 genome ? AF: 0.000466 AC: 71AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35AN XY: 74460
ClinVar
Submissions by phenotype
Combined oxidative phosphorylation defect type 14 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 23, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 324 of the FARS2 protein (p.Tyr324Cys). This variant is present in population databases (rs142073519, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with FARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 214333). 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 FARS2 protein function. 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 provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 07, 2014 | p.Tyr324Cys (TAC>TGC): c.971 A>G in exon 5 of the FARS2 gene (NM_006567.3). The Y324C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The Y324C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (D325Y and I329T) have been reported in association with epilepsy, infantile-onset and mitochondrial encephalopathy, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at