rs760345680
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_024417.5(FDXR):c.1156C>T(p.Arg386Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000409 in 1,613,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000043 ( 0 hom. )
Consequence
FDXR
NM_024417.5 missense
NM_024417.5 missense
Scores
4
8
3
Clinical Significance
Conservation
PhyloP100: 4.67
Genes affected
FDXR (HGNC:3642): (ferredoxin reductase) This gene encodes a mitochondrial flavoprotein that initiates electron transport for cytochromes P450 receiving electrons from NADPH. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-74863914-G-A is Pathogenic according to our data. Variant chr17-74863914-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.39121622). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FDXR | NM_024417.5 | c.1156C>T | p.Arg386Trp | missense_variant | 10/12 | ENST00000293195.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FDXR | ENST00000293195.10 | c.1156C>T | p.Arg386Trp | missense_variant | 10/12 | 1 | NM_024417.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152142Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000180 AC: 45AN: 250556Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135372
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Auditory neuropathy-optic atrophy syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 13, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 05, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 19, 2020 | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with auditory neuropathy and optic atrophy (MIM#617717). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (45 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (6 heterozygotes, 0 homozygotes). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated NAD(P) binding domain (PMID: 29040572). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple homozygous patients with mitochondriopathy with optic atrophy (ClinVar, PMID: 29040572). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. This variant causes reduced enzyme activity and overall mitochondrial dysfunction. Defects were rescued by overexpression of WT FDXR (PMID: 29040572). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
FDXR-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant is also known as p.Arg386Trp, p.Arg392Trp, or p.Arg378Trp in the literature. This variant has been previously reported as a homozygous and a compound heterozygous change in patients with Mitochondriopathy with optic atrophy (PMID: 29040572, 33348459). Functional studies in patient fibroblasts indicate that the p.Arg429Trp variant decreases FDXR protein levels, and in vitro studies demonstrate that the variant leads to mitochondrial dysfunction (PMID: 29040572). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.02% (45/250556) and thus is presumed to be rare. The c.1285C>T (p.Arg429Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1285C>T (p.Arg429Trp) variant is classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 08, 2023 | The FDXR c.1156C>T variant is predicted to result in the amino acid substitution p.Arg386Trp. This variant has been reported as pathogenic for autosomal recessive mitochondriopathy with optic atrophy (seven homozygotes and one compound heterozygote from six unrelated families), representing 42% (11 of 26) of pathogenic variants identified in this study (described as p.R392W, Peng et al. 2017. PubMed ID: 29040572). This variant was also reported in the homozygous state in two additional patients from unrelated families with features consistent with FDXR-related disease, and was reported to result in a moderately severe phenotype in comparison to other homozygous pathogenic variants (Stenton. 2021. PubMed ID: 33348459; described as p.Arg392Trp, O'Brien et al. 2021. PubMed ID: 34906498). Functional studies found this variant led to deficient ferredoxin NADP reductase activity and mitochondrial dysfunction in patient fibroblasts (Peng et al. 2017. PubMed ID: 29040572). This variant is reported in 0.13% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-72860036-G-A). In ClinVar this variant is listed as pathogenic (2) and likely pathogenic (1) by other clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/520994/). We interpret this variant as likely pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 12, 2017 | - - |
MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 9B Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 16, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
REVEL
Uncertain
Sift4G
Pathogenic
D;D;D;D;D;D;D;D
Vest4
MVP
MPC
0.53
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Name
Calibrated prediction
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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