rs770035560
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_006567.5(FARS2):c.253C>G(p.Pro85Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,888 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
FARS2
NM_006567.5 missense
NM_006567.5 missense
Scores
11
6
1
Clinical Significance
Conservation
PhyloP100: 7.57
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 Likely_pathogenic. Variant got 7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.961
PP5
?
Variant 6-5368823-C-G is Pathogenic according to our data. Variant chr6-5368823-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 587669.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FARS2 | NM_006567.5 | c.253C>G | p.Pro85Ala | missense_variant | 2/7 | ENST00000274680.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FARS2 | ENST00000274680.9 | c.253C>G | p.Pro85Ala | missense_variant | 2/7 | 1 | NM_006567.5 | P1 | |
FARS2 | ENST00000324331.10 | c.253C>G | p.Pro85Ala | missense_variant | 2/7 | 1 | P1 | ||
FARS2 | ENST00000648580.1 | c.253C>G | p.Pro85Ala | missense_variant, NMD_transcript_variant | 2/9 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251294Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135852
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727244
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Combined oxidative phosphorylation defect type 14 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2021 | This variant has been reported to affect FARS2 protein function (PMID: 27095821). 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. This variant has been observed in combination with another FARS2 variant in an individual affected with juvenile onset refractory epilepsy and progressive myoclonus (PMID: 27095821). ClinVar contains an entry for this variant (Variation ID: 587669). This variant is present in population databases (rs770035560, ExAC 0.002%). This sequence change replaces proline with alanine at codon 85 of the FARS2 protein (p.Pro85Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Jun 13, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0365);Gain of MoRF binding (P = 0.0365);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at