17-74866471-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024417.5(FDXR):​c.368A>G​(p.Gln123Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.795 in 1,612,948 control chromosomes in the GnomAD database, including 512,443 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.83 (52960 hom., cov: 34)
  • Exomes 𝑓: 0.79 (459483 hom.)
• Consequence: FDXR NM_024417.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005993098).
• BP6: Variant 17-74866471-T-C is Benign according to our data. Variant chr17-74866471-T-C is described in ClinVar as Benign. ClinVar VariationId is 769225.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

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>G	p.Gln123Arg	missense	Exon 4 of 12	NP_077728.3
	FDXR	NM_001258012.4		c.497A>G	p.Gln166Arg	missense	Exon 4 of 12	NP_001244941.2
	FDXR	NM_001258013.4		c.461A>G	p.Gln154Arg	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>G	p.Gln123Arg	missense	Exon 4 of 12	ENSP00000293195.5
	FDXR	ENST00000581530.5	TSL:1	c.368A>G	p.Gln123Arg	missense	Exon 4 of 12	ENSP00000462972.1
	FDXR	ENST00000578473.5	TSL:1	n.1056A>G		non_coding_transcript_exon	Exon 4 of 12

Frequencies

GnomAD3 genomes AF: 0.829 AC: 126106 AN: 152090 Hom.: 52899 Cov.: 34

Gnomad AFR AF: 0.940

Gnomad AMI AF: 0.881

Gnomad AMR AF: 0.839

Gnomad ASJ AF: 0.663

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.808

Gnomad FIN AF: 0.816

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.790

Gnomad OTH AF: 0.807

GnomAD4 exome AF: 0.791 AC: 1155779 AN: 1460740 Hom.: 459483 Cov.: 72 AF XY: 0.790 AC XY: 574313 AN XY: 726640

African (AFR) AF: 0.946 AC: 31666 AN: 33456

American (AMR) AF: 0.862 AC: 38477 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 17384 AN: 26108

East Asian (EAS) AF: 0.577 AC: 22867 AN: 39644

South Asian (SAS) AF: 0.806 AC: 69486 AN: 86208

European-Finnish (FIN) AF: 0.818 AC: 43277 AN: 52930

Middle Eastern (MID) AF: 0.723 AC: 4171 AN: 5768

European-Non Finnish (NFE) AF: 0.793 AC: 881030 AN: 1111604

Other (OTH) AF: 0.785 AC: 47421 AN: 60372

GnomAD4 genome AF: 0.829 AC: 126223 AN: 152208 Hom.: 52960 Cov.: 34 AF XY: 0.830 AC XY: 61747 AN XY: 74400

African (AFR) AF: 0.940 AC: 39064 AN: 41542

American (AMR) AF: 0.840 AC: 12847 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 2300 AN: 3470

East Asian (EAS) AF: 0.593 AC: 3059 AN: 5162

South Asian (SAS) AF: 0.808 AC: 3894 AN: 4822

European-Finnish (FIN) AF: 0.816 AC: 8643 AN: 10594

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.790 AC: 53689 AN: 68002

Other (OTH) AF: 0.807 AC: 1702 AN: 2110

Alfa AF: 0.799 Hom.: 41794

Bravo AF: 0.832

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_noAF	Uncertain	0.12
CADD	Benign	0.024
DEOGEN2	Benign	0.0028	T
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0060	T
PhyloP100		-1.3
Sift4G	Benign	1.0	T
Vest4		0.091
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
gMVP		0.45

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs690514; hg19: chr17-72862593;