chr17-74863914-G-A

Position:

chr17-74863914-G-A

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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.67

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 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	Protein	UniProt
FDXR	NM_024417.5 linkuse as main transcript	c.1156C>T	p.Arg386Trp	missense_variant	10/12	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.1156C>T	p.Arg386Trp	missense_variant	10/12	1	NM_024417.5	ENSP00000293195	P3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000180

AC:

AN:

250556

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135372

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00127

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1461194

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

726858

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.000189

AC:

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. -

Multiple mitochondrial dysfunctions syndrome 9b

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 16, 2024

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

0.0033

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

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

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.39

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.18

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-7.3

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

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Vest4

0.76

MVP

0.81

MPC

0.53

ClinPred

0.97

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.93

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