rs138034837
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5
The NM_000144.5(FXN):c.493C>T(p.Arg165Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,840 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). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Consequence
NM_000144.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FXN | NM_000144.5 | c.493C>T | p.Arg165Cys | missense_variant | 5/5 | ENST00000484259.3 | |
FXN | NM_181425.3 | c.501C>T | p.Ser167= | synonymous_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FXN | ENST00000484259.3 | c.493C>T | p.Arg165Cys | missense_variant | 5/5 | 3 | NM_000144.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461840Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1AN XY: 727222
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
FXN-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 05, 2024 | The FXN c.493C>T variant is predicted to result in the amino acid substitution p.Arg165Cys. This variant was reported in the compound heterozygous state with a GAA expansion in two individuals with Friedreich ataxia (Forrest et al. 1998. PubMed ID: 10732799; McCormack et al. 2000. PubMed ID: 10766903). This variant has also been reported in the homozygous state in three siblings with Charcot-Marie-Tooth disease (Candayan et al. 2019. PubMed ID: 31673878), and was shown to impair protein function (Bridwell-Rabb et al. 2011. PubMed ID: 21776984; Clark et al. 2017. PubMed ID: 28812047). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. - |
Charcot-Marie-Tooth-like disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CMT Laboratory, Bogazici University | Dec 01, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at