rs752143061

Positions:

chr17-74864234-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_ModeratePM2PP3PP5_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

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.81

Variant links:

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]

FDXR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
FDXR	NM_024417.5 linkuse as main transcript	c.916C>T	p.Arg306Cys	missense_variant	9/12	ENST00000293195.10	NP_077728.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FDXR	ENST00000293195.10 linkuse as main transcript	c.916C>T	p.Arg306Cys	missense_variant	9/12	1	NM_024417.5	ENSP00000293195	P3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

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:

AN:

241968

Hom.:

AF XY:

0.0000226

AC XY:

AN XY:

132768

show subpopulations

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:

AN:

1455194

Hom.:

Cov.:

AF XY:

0.0000346

AC XY:

AN XY:

722710

show subpopulations

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:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74478

show subpopulations

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.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Auditory neuropathy-optic atrophy syndrome

Pathogenic:2

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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 12, 2017	- -

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. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 2023

Not observed at significant frequency in large population cohorts (gnomAD); 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: 28965846, 33348459, 33938912) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

.;.;.;.;T;.;T;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.097

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.76

D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.71

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.7

.;D;D;.;.;D;.;D

REVEL

Benign

0.21

Sift

Benign

0.044

.;D;D;.;.;D;.;T

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over