rs199863563
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4
The NM_006567.5(FARS2):c.407C>A(p.Pro136His) variant causes a missense change. The variant allele was found at a frequency of 0.000181 in 1,614,018 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P136L) has been classified as Uncertain significance.
Frequency
Consequence
NM_006567.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FARS2 | NM_006567.5 | c.407C>A | p.Pro136His | missense_variant | 2/7 | ENST00000274680.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FARS2 | ENST00000274680.9 | c.407C>A | p.Pro136His | missense_variant | 2/7 | 1 | NM_006567.5 | P1 | |
FARS2 | ENST00000324331.10 | c.407C>A | p.Pro136His | missense_variant | 2/7 | 1 | P1 | ||
FARS2 | ENST00000648580.1 | c.407C>A | p.Pro136His | missense_variant, NMD_transcript_variant | 2/9 |
Frequencies
GnomAD3 genomes AF: 0.000191 AC: 29AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000306 AC: 77AN: 251328Hom.: 0 AF XY: 0.000287 AC XY: 39AN XY: 135854
GnomAD4 exome AF: 0.000180 AC: 263AN: 1461878Hom.: 1 Cov.: 32 AF XY: 0.000175 AC XY: 127AN XY: 727244
GnomAD4 genome AF: 0.000191 AC: 29AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74318
ClinVar
Submissions by phenotype
Combined oxidative phosphorylation defect type 14 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Jun 13, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 23, 2024 | This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 136 of the FARS2 protein (p.Pro136His). This variant is present in population databases (rs199863563, gnomAD 0.6%). This missense change has been observed in individual(s) with spastic paraplegia (PMID: 30250868; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 473309). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FARS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects FARS2 function (PMID: 30250868). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2022 | Functional studies show that this variant is associated with significantly reduced enzyme activity compared to wild type (Sahai SK et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30250868, 31692161) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at