17-74863112-C-T

Variant names:

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

Variant summary

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

The NM_024417.5(FDXR):​c.1309G>A​(p.Gly437Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: FDXR NM_024417.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• 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>A	p.Gly437Ser	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>A	p.Gly437Ser	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

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Auditory neuropathy-optic atrophy syndrome Pathogenic:1

Mar 01, 2023

Genetic and Metabolic Disease Program, Children's Medical Center Research Institute, UT Southwestern Medical Center at Dallas

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

May 26, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	.;.;.;.;T;.;T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.98	T
PhyloP100		5.5
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.9	.;D;D;.;.;D;.;D
REVEL	Benign	0.21
Sift	Uncertain	0.0030	.;D;D;.;.;D;.;D
Sift4G	Uncertain	0.033	D;D;D;D;D;D;D;T
Vest4		0.64
MutPred		0.42		Loss of helix (P = 0.0123);.;.;.;.;.;.;.;
MVP		0.56
MPC		0.60
ClinPred		0.99	D
GERP RS		3.8
gMVP		0.87
Mutation Taster		=0/100	disease causing

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;