chr17-74866471-T-G

Variant names:

• chr17-74866471-T-G
• rs690514
• NM_024417.5:c.368A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024417.5(FDXR):​c.368A>C​(p.Gln123Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. Q123R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: FDXR NM_024417.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.30
• Publications: 32 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09814799).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FDXR	NM_024417.5	MANE Select	c.368A>C	p.Gln123Pro	missense	Exon 4 of 12	NP_077728.3
	FDXR	NM_001258012.4		c.497A>C	p.Gln166Pro	missense	Exon 4 of 12	NP_001244941.2
	FDXR	NM_001258013.4		c.461A>C	p.Gln154Pro	missense	Exon 5 of 13	NP_001244942.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FDXR	ENST00000293195.10	TSL:1 MANE Select	c.368A>C	p.Gln123Pro	missense	Exon 4 of 12	ENSP00000293195.5
	FDXR	ENST00000581530.5	TSL:1	c.368A>C	p.Gln123Pro	missense	Exon 4 of 12	ENSP00000462972.1
	FDXR	ENST00000578473.5	TSL:1	n.1056A>C		non_coding_transcript_exon	Exon 4 of 12

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 72

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 41794

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DEOGEN2	Benign	0.050	T
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.098	T
PhyloP100		-1.3
Sift4G	Uncertain	0.018	D
Vest4		0.45
gMVP		0.87

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: rs690514; hg19: chr17-72862593;