rs752143061

chr17-74864234-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_Moderate PM2 PP3 PP5_Very_Strong

The NM_024417.5(FDXR):c.916C>T(p.Arg306Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000411 in 1,607,488 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: FDXR NM_024417.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.81

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS1: Transcript NM_024417.5 (FDXR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764
• PP5: Variant 17-74864234-G-A is Pathogenic according to our data. Variant chr17-74864234-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 441237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-74864234-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FDXR	NM_024417.5	c.916C>T	p.Arg306Cys	missense_variant	9/12	ENST00000293195.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FDXR	ENST00000293195.10	c.916C>T	p.Arg306Cys	missense_variant	9/12	1	NM_024417.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000289 AC: 7 AN: 241968 Hom.: 0 AF XY: 0.0000226 AC XY: 3 AN XY: 132768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000874

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000372

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000405 AC: 59 AN: 1455194 Hom.: 0 Cov.: 34 AF XY: 0.0000346 AC XY: 25 AN XY: 722710

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000451

Gnomad4 OTH exome AF: 0.0000500

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74478

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Auditory neuropathy-optic atrophy syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 12, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 26, 2018	The p.Arg337Cys variant in FDXR (also known as p.Arg306Cys) has been reported in 1 homozygous individual and 1 compound heterozygous individual with auditory n europathy and optic atrophy (Paul 2017). The variant segregated with disease in 3 relatives (Paul 2017). In vivo functional studies in yeast provide some eviden ce that the p.Arg337Cys variant may impact protein function (Paul 2017). However , these types of assays may not accurately represent biological function. This v ariant has been identified in 3/34332 Latino and 4/107544 European chromosomes b y the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Co mputational prediction tools and conservation analysis do not provide strong sup port for or against an impact to the protein. In summary, although additional st udies are required to fully establish its clinical significance, the p.Arg337Cys variant is likely pathogenic. ACMG/AMP criteria applied: PP1_Strong, PM2, PM3, PS3_Supporting. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

The c.934C>T (p.R312C) alteration is located in exon 9 (coding exon 9) of the FDXR gene. This alteration results from a C to T substitution at nucleotide position 934, causing the arginine (R) at amino acid position 312 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (7/241968) total alleles studied. The highest observed frequency was 0.01% (3/34332) of Latino alleles. This alteration was detected in conjunction with another pathogenic FDXR mutation in an individual with bilateral auditory neuropathy, adolescent-onset hearing defects, and bilateral optic atrophy. In addition, this alteration was detected in the homozygous state and segregated with disease among multiple individuals in one family who had clinical features consistent with FDXR-related mitochondrial encephalomyopathy (Paul, 2017). This amino acid position is well conserved in available vertebrate species. Functional assays in patient fibroblasts show aberrant ferredoxin reductase levels, respiratory chain enzyme activity, and iron uptake (Paul, 2017). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Benign	0.16
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
REVEL	Benign	0.21
Sift4G	Benign	0.083	T;T;T;T;T;T;T;T
Vest4		0.73
MutPred		0.58		Loss of MoRF binding (P = 0.0069);.;.;.;.;.;.;.;
MVP		0.96
MPC		0.41
ClinPred		0.61	D
GERP RS		3.6
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752143061; hg19: chr17-72860356;