rs761360080
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_006567.5(FARS2):c.411C>A(p.Ser137Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,056 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
FARS2
NM_006567.5 missense
NM_006567.5 missense
Scores
8
10
1
Clinical Significance
Conservation
PhyloP100: 3.14
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.924
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FARS2 | NM_006567.5 | c.411C>A | p.Ser137Arg | missense_variant | 2/7 | ENST00000274680.9 | NP_006558.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FARS2 | ENST00000274680.9 | c.411C>A | p.Ser137Arg | missense_variant | 2/7 | 1 | NM_006567.5 | ENSP00000274680.4 | ||
FARS2 | ENST00000324331.10 | c.411C>A | p.Ser137Arg | missense_variant | 2/7 | 1 | ENSP00000316335.5 | |||
FARS2 | ENST00000648580.1 | n.411C>A | non_coding_transcript_exon_variant | 2/9 | ENSP00000497889.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152168Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251312Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135844
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727248
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74324
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Combined oxidative phosphorylation defect type 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 14, 2020 | Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably 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. This variant has not been reported in the literature in individuals with FARS2-related disease. This variant is present in population databases (rs761360080, ExAC 0.002%). This sequence change replaces serine with arginine at codon 137 of the FARS2 protein (p.Ser137Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2024 | The c.411C>A (p.S137R) alteration is located in exon 2 (coding exon 1) of the FARS2 gene. This alteration results from a C to A substitution at nucleotide position 411, causing the serine (S) at amino acid position 137 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H;H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Loss of ubiquitination at K139 (P = 0.0237);Loss of ubiquitination at K139 (P = 0.0237);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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