17-74863112-C-G

Variant names:

• chr17-74863112-C-G
• rs766147142
• NM_024417.5:c.1309G>C

Variant summary

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

The NM_024417.5(FDXR):​c.1309G>C​(p.Gly437Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G437S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: FDXR NM_024417.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.51
• Publications: 6 publications found

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: PanelApp Australia, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FDXR	NM_024417.5	c.1309G>C	p.Gly437Arg	missense_variant	Exon 11 of 12	ENST00000293195.10	NP_077728.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FDXR	ENST00000293195.10	c.1309G>C	p.Gly437Arg	missense_variant	Exon 11 of 12	1	NM_024417.5	ENSP00000293195.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	.;.;.;.;T;.;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.92	T
PhyloP100		5.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.8	.;D;D;.;.;D;.;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	.;D;D;.;.;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D
Vest4		0.74
MutPred		0.52		Gain of helix (P = 0.0078);.;.;.;.;.;.;.;
MVP		0.57
MPC		0.88
ClinPred		0.99	D
GERP RS		3.8
gMVP		0.94

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

Other links and lift over

dbSNP: rs766147142; hg19: chr17-72859234;