Genetic Variant FDXR:p.Glu477Lys (chr17-74862864-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024417.5(FDXR):c.1429G>A(p.Glu477Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FDXR
NM_024417.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 7.07

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

auditory neuropathy-optic atrophy syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FDXR links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024417.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FDXR	NM_024417.5	MANE Select	c.1429G>A	p.Glu477Lys	missense	Exon 12 of 12	NP_077728.3	A0A0C4DFN8
FDXR	NM_001258012.4		c.1558G>A	p.Glu520Lys	missense	Exon 12 of 12	NP_001244941.2	A0A0A0MT64
FDXR	NM_001258013.4		c.1522G>A	p.Glu508Lys	missense	Exon 13 of 13	NP_001244942.2	A0A0A0MSZ4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FDXR	ENST00000293195.10	TSL:1 MANE Select	c.1429G>A	p.Glu477Lys	missense	Exon 12 of 12	ENSP00000293195.5	A0A0C4DFN8
FDXR	ENST00000581530.5	TSL:1	c.1447G>A	p.Glu483Lys	missense	Exon 12 of 12	ENSP00000462972.1	A0A0C4DGN7
FDXR	ENST00000578473.5	TSL:1	n.2117G>A		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460740

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726718

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111954

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Auditory neuropathy-optic atrophy syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.93

PhyloP100

7.1

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.22

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0060

Vest4

0.74

MutPred

0.41

Gain of MoRF binding (P = 0.0025)

MVP

0.49

MPC

0.92

ClinPred

1.0

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.92

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over