chr17-74862834-G-A

Position:

chr17-74862834-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_024417.5(FDXR):c.1459C>T(p.Arg487Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000754 in 1,611,354 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00078 ( 2 hom. )

Consequence

FDXR
NM_024417.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.51

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05139652).

BP6

Variant 17-74862834-G-A is Benign according to our data. Variant chr17-74862834-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1699164.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FDXR	NM_024417.5 linkuse as main transcript	c.1459C>T	p.Arg487Cys	missense_variant	12/12	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.1459C>T	p.Arg487Cys	missense_variant	12/12	1	NM_024417.5	ENSP00000293195	P3

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000809

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000467

AC:

116

AN:

248514

Hom.:

AF XY:

0.000430

AC XY:

AN XY:

134774

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.000543

Gnomad NFE exome

AF:

0.000710

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000781

AC:

1140

AN:

1459062

Hom.:

Cov.:

AF XY:

0.000774

AC XY:

562

AN XY:

725944

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000441

Gnomad4 FIN exome

AF:

0.000568

Gnomad4 NFE exome

AF:

0.000921

Gnomad4 OTH exome

AF:

0.000564

GnomAD4 genome

AF:

0.000492

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000517

Hom.:

Bravo

AF:

0.000491

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000560

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.1477C>T (p.R493C) alteration is located in exon 12 (coding exon 12) of the FDXR gene. This alteration results from a C to T substitution at nucleotide position 1477, causing the arginine (R) at amino acid position 493 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Auditory neuropathy-optic atrophy syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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 cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (136 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

FDXR: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

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

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.97

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

M_CAP

Benign

0.084

MetaRNN

Benign

0.051

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

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-3.4

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

REVEL

Benign

0.098

Sift

Uncertain

0.0060

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

Sift4G

Uncertain

0.019

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

Vest4

0.18

MVP

0.42

MPC

0.83

ClinPred

0.073

GERP RS

-0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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