17-74866908-C-T

Variant names:

• chr17-74866908-C-T
• rs1688149
• NM_024417.5:c.178-32G>A

Variant summary

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

The NM_001258012.4(FDXR):​c.275G>A​(p.Gly92Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.794 in 1,606,128 control chromosomes in the GnomAD database, including 508,827 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.83 (52780 hom., cov: 32)
  • Exomes 𝑓: 0.79 (456047 hom.)
• Consequence: FDXR NM_001258012.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.936
• Publications: 17 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=0.004830122).
• BP6: Variant 17-74866908-C-T is Benign according to our data. Variant chr17-74866908-C-T is described in ClinVar as Benign. ClinVar VariationId is 769224.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258012.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FDXR	NM_024417.5	MANE Select	c.178-32G>A		intron	N/A	NP_077728.3
	FDXR	NM_001258012.4		c.275G>A	p.Gly92Asp	missense	Exon 3 of 12	NP_001244941.2
	FDXR	NM_001258013.4		c.271-32G>A		intron	N/A	NP_001244942.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FDXR	ENST00000293195.10	TSL:1 MANE Select	c.178-32G>A		intron	N/A	ENSP00000293195.5
	FDXR	ENST00000581530.5	TSL:1	c.178-32G>A		intron	N/A	ENSP00000462972.1
	FDXR	ENST00000578473.5	TSL:1	n.863-29G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.828 AC: 125873 AN: 152036 Hom.: 52721 Cov.: 32

Gnomad AFR AF: 0.940

Gnomad AMI AF: 0.882

Gnomad AMR AF: 0.836

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.805

Gnomad FIN AF: 0.816

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.788

Gnomad OTH AF: 0.805

GnomAD4 exome AF: 0.790 AC: 1148778 AN: 1453972 Hom.: 456047 Cov.: 57 AF XY: 0.789 AC XY: 570251 AN XY: 722568

African (AFR) AF: 0.946 AC: 31594 AN: 33388

American (AMR) AF: 0.859 AC: 37411 AN: 43532

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 17166 AN: 25972

East Asian (EAS) AF: 0.575 AC: 22597 AN: 39300

South Asian (SAS) AF: 0.804 AC: 68326 AN: 85020

European-Finnish (FIN) AF: 0.817 AC: 43159 AN: 52826

Middle Eastern (MID) AF: 0.721 AC: 4151 AN: 5758

European-Non Finnish (NFE) AF: 0.792 AC: 877285 AN: 1108074

Other (OTH) AF: 0.783 AC: 47089 AN: 60102

GnomAD4 genome AF: 0.828 AC: 125988 AN: 152156 Hom.: 52780 Cov.: 32 AF XY: 0.829 AC XY: 61640 AN XY: 74380

African (AFR) AF: 0.940 AC: 39054 AN: 41538

American (AMR) AF: 0.837 AC: 12797 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2279 AN: 3472

East Asian (EAS) AF: 0.588 AC: 3029 AN: 5148

South Asian (SAS) AF: 0.805 AC: 3884 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: 0.788 AC: 53577 AN: 67962

Other (OTH) AF: 0.802 AC: 1698 AN: 2116

Alfa AF: 0.797 Hom.: 9094

Bravo AF: 0.831

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.5
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0048	T
PhyloP100		-0.94
Sift4G	Benign	0.44	T
Vest4		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
gMVP		0.39

Splicing

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

Other links and lift over

dbSNP: rs1688149; hg19: chr17-72863030;