NM_024417.5:c.643C>G

Variant names:

• chr17-74864898-G-C
• rs1555620021
• NM_024417.5:c.643C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_024417.5(FDXR):​c.643C>G​(p.Leu215Val) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FDXR NM_024417.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.32
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778
• PP5: Variant 17-74864898-G-C is Pathogenic according to our data. Variant chr17-74864898-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 441239.Status of the report is no_assertion_criteria_provided, 0 stars.

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.643C>G	p.Leu215Val	missense	Exon 7 of 12	NP_077728.3
	FDXR	NM_001258012.4		c.772C>G	p.Leu258Val	missense	Exon 7 of 12	NP_001244941.2
	FDXR	NM_001258013.4		c.736C>G	p.Leu246Val	missense	Exon 8 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.643C>G	p.Leu215Val	missense	Exon 7 of 12	ENSP00000293195.5
	FDXR	ENST00000581530.5	TSL:1	c.661C>G	p.Leu221Val	missense	Exon 7 of 12	ENSP00000462972.1
	FDXR	ENST00000578473.5	TSL:1	n.1331C>G		non_coding_transcript_exon	Exon 7 of 12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Auditory neuropathy-optic atrophy syndrome Pathogenic:1

Oct 12, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.34	D
PhyloP100		2.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Vest4		0.52
MutPred		0.44		Gain of MoRF binding (P = 0.097)
MVP		0.92
MPC		0.86
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.78
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs1555620021; hg19: chr17-72861020;