rs372054960
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5
The NM_006567.5(FARS2):c.1220C>T(p.Thr407Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000217 in 1,613,972 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T407T) has been classified as Likely benign.
Frequency
Consequence
NM_006567.5 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 |
---|---|---|---|---|---|---|---|
FARS2 | NM_006567.5 | c.1220C>T | p.Thr407Met | missense_variant, splice_region_variant | 7/7 | ENST00000274680.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FARS2 | ENST00000274680.9 | c.1220C>T | p.Thr407Met | missense_variant, splice_region_variant | 7/7 | 1 | NM_006567.5 | P1 | |
FARS2 | ENST00000324331.10 | c.1220C>T | p.Thr407Met | missense_variant, splice_region_variant | 7/7 | 1 | P1 | ||
FARS2 | ENST00000648580.1 | c.1218-50415C>T | intron_variant, NMD_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152212Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000479 AC: 12AN: 250438Hom.: 0 AF XY: 0.0000591 AC XY: 8AN XY: 135454
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461760Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727192
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74352
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2014 | p.Thr407Met (ACG>ATG): c.1220 C>T in exon 7 of the FARS2 gene (NM_006567.3). The T407M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The T407M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity and size. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. 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). - |
Combined oxidative phosphorylation defect type 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 07, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 407 of the FARS2 protein (p.Thr407Met). This variant is present in population databases (rs372054960, gnomAD 0.04%). 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: 214331). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at