chr6-5369037-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_006567.5(FARS2):c.467C>T(p.Thr156Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,154 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T156T) has been classified as Benign.
Frequency
Consequence
NM_006567.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FARS2 | NM_006567.5 | c.467C>T | p.Thr156Met | missense_variant | 2/7 | ENST00000274680.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FARS2 | ENST00000274680.9 | c.467C>T | p.Thr156Met | missense_variant | 2/7 | 1 | NM_006567.5 | P1 | |
FARS2 | ENST00000324331.10 | c.467C>T | p.Thr156Met | missense_variant | 2/7 | 1 | P1 | ||
FARS2 | ENST00000648580.1 | c.467C>T | p.Thr156Met | missense_variant, NMD_transcript_variant | 2/9 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000876 AC: 22AN: 251250Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135838
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 727242
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74454
ClinVar
Submissions by phenotype
Combined oxidative phosphorylation defect type 14 Pathogenic:2
Likely pathogenic, 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 17, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 156 of the FARS2 protein (p.Thr156Met). This variant is present in population databases (rs146988468, gnomAD 0.06%). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 27652284, 33972171). 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: 587677). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FARS2 protein function. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | FARS2: PM3:Strong, PM2 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at