17-74862937-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_024417.5(FDXR):c.1356A>G(p.Pro452=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,612,124 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (44 hom., cov: 34)
  • Exomes 𝑓: 0.0014 (35 hom.)
• Consequence: FDXR NM_024417.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.59

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 17-74862937-T-C is Benign according to our data. Variant chr17-74862937-T-C is described in ClinVar as [Benign]. Clinvar id is 785578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0126 (1918/152346) while in subpopulation AFR AF= 0.0426 (1773/41578). AF 95% confidence interval is 0.041. There are 44 homozygotes in gnomad4. There are 911 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FDXR	NM_024417.5	c.1356A>G	p.Pro452=	synonymous_variant	12/12	ENST00000293195.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FDXR	ENST00000293195.10	c.1356A>G	p.Pro452=	synonymous_variant	12/12	1	NM_024417.5	P3

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1910 AN: 152228 Hom.: 45 Cov.: 34

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00680

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00325 AC: 809 AN: 249136 Hom.: 20 AF XY: 0.00226 AC XY: 306 AN XY: 135118

Gnomad AFR exome AF: 0.0429

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000491

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.00141 AC: 2063 AN: 1459778 Hom.: 35 Cov.: 29 AF XY: 0.00127 AC XY: 924 AN XY: 726310

Gnomad4 AFR exome AF: 0.0429

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.000261

Gnomad4 OTH exome AF: 0.00315

GnomAD4 genome AF: 0.0126 AC: 1918 AN: 152346 Hom.: 44 Cov.: 34 AF XY: 0.0122 AC XY: 911 AN XY: 74506

Gnomad4 AFR AF: 0.0426

Gnomad4 AMR AF: 0.00679

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00650 Hom.: 9

Bravo AF: 0.0145

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FDXR-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	15
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: -14

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

Publications

LitVar

Other links and lift over

dbSNP: rs34435361; hg19: chr17-72859059;