chr6-5613259-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006567.5(FARS2):c.1156C>T(p.Arg386Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000806 in 1,613,180 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
FARS2
NM_006567.5 stop_gained
NM_006567.5 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.20
Genes affected
FARS2 (HGNC:21062): (phenylalanyl-tRNA synthetase 2, mitochondrial) This gene encodes a protein that transfers phenylalanine to its cognate tRNA. This protein localizes to the mitochondrion and plays a role in mitochondrial protein translation. Mutations in this gene can cause combined oxidative phosphorylation deficiency 14 (Alpers encephalopathy). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-5613259-C-T is Pathogenic according to our data. Variant chr6-5613259-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1073793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FARS2 | NM_006567.5 | c.1156C>T | p.Arg386Ter | stop_gained | 6/7 | ENST00000274680.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FARS2 | ENST00000274680.9 | c.1156C>T | p.Arg386Ter | stop_gained | 6/7 | 1 | NM_006567.5 | P1 | |
FARS2 | ENST00000324331.10 | c.1156C>T | p.Arg386Ter | stop_gained | 6/7 | 1 | P1 | ||
FARS2 | ENST00000648580.1 | c.1156C>T | p.Arg386Ter | stop_gained, NMD_transcript_variant | 6/9 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152120Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251120Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135728
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461060Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 726858
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152120Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74302
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Combined oxidative phosphorylation defect type 14 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change creates a premature translational stop signal (p.Arg386*) in the FARS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FARS2 are known to be pathogenic (PMID: 22833457). This variant is present in population databases (rs770597592, gnomAD 0.004%). 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: 1073793). For these reasons, this variant has been classified as Pathogenic. - |
FARS2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 30, 2024 | Variant summary: FARS2 c.1156C>T (p.Arg386X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 1.2e-05 in 251120 control chromosomes. c.1156C>T has been reported in the literature as a single heterozygous variant of FARS2 in an individual affected with complex hereditary Sensory Neuropathy (Travaglini_2018). These report(s) do not provide unequivocal conclusions about association of the variant with FARS2-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29691679). ClinVar contains an entry for this variant (Variation ID: 1073793). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at