rs746953590
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_024417.5(FDXR):c.221C>T(p.Pro74Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,078 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
Consequence
NM_024417.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FDXR | NM_024417.5 | c.221C>T | p.Pro74Leu | missense_variant | 3/12 | ENST00000293195.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FDXR | ENST00000293195.10 | c.221C>T | p.Pro74Leu | missense_variant | 3/12 | 1 | NM_024417.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250916Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135748
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461864Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727224
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74360
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 17, 2018 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 02, 2021 | Not observed in large population cohorts (Lek et al., 2016); 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: 29040572, 33348459) - |
Auditory neuropathy-optic atrophy syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000520993, PMID:29040572). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000159). A missense variant is a common mechanism associated with Auditory neuropathy and optic atrophy. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
FDXR-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 30, 2023 | The FDXR c.221C>T variant is predicted to result in the amino acid substitution p.Pro74Leu. This variant has been reported in the heterozygous state, along with the p.Arg386Trp variant, in an individual with mitochondriopathy and optic atrophy (Table 1, Peng et al. 2017. PubMed ID: 29040572). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at