rs761709212
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006567.5(FARS2):c.801C>G(p.Tyr267Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000124 in 1,613,774 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
FARS2
NM_006567.5 stop_gained
NM_006567.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.81
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 6-5431069-C-G is Pathogenic according to our data. Variant chr6-5431069-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 522083.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.801C>G | p.Tyr267Ter | stop_gained | 4/7 | ENST00000274680.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FARS2 | ENST00000274680.9 | c.801C>G | p.Tyr267Ter | stop_gained | 4/7 | 1 | NM_006567.5 | P1 | |
FARS2 | ENST00000324331.10 | c.801C>G | p.Tyr267Ter | stop_gained | 4/7 | 1 | P1 | ||
FARS2 | ENST00000445533.1 | c.189C>G | p.Tyr63Ter | stop_gained | 2/3 | 3 | |||
FARS2 | ENST00000648580.1 | c.801C>G | p.Tyr267Ter | stop_gained, NMD_transcript_variant | 4/9 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251250Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135794
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461570Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727080
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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 | Oct 09, 2019 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in FARS2 are known to be pathogenic (PMID: 22833457). This variant has not been reported in the literature in individuals with FARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 522083). This variant is present in population databases (rs761709212, ExAC 0.009%). This sequence change creates a premature translational stop signal (p.Tyr267*) in the FARS2 gene. It is expected to result in an absent or disrupted protein product. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 25, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
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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