17-74862879-T-C

Position:

• chr17-74862879-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000293195.10(FDXR):​c.1414A>G​(p.Thr472Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00561 in 1,613,208 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0057 (29 hom.)
• Consequence: FDXR ENST00000293195.10 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.53

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003815323).
• BP6: Variant 17-74862879-T-C is Benign according to our data. Variant chr17-74862879-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 779367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00458 (697/152292) while in subpopulation NFE AF= 0.00794 (540/68004). AF 95% confidence interval is 0.00739. There are 2 homozygotes in gnomad4. There are 308 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FDXR	NM_024417.5	c.1414A>G	p.Thr472Ala	missense_variant	12/12	ENST00000293195.10	NP_077728.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FDXR	ENST00000293195.10	c.1414A>G	p.Thr472Ala	missense_variant	12/12	1	NM_024417.5	ENSP00000293195	P3

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 697 AN: 152174 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00794

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00441 AC: 1105 AN: 250362 Hom.: 5 AF XY: 0.00458 AC XY: 621 AN XY: 135588

Gnomad AFR exome AF: 0.000804

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00468

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00444

Gnomad FIN exome AF: 0.00122

Gnomad NFE exome AF: 0.00695

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00571 AC: 8347 AN: 1460916 Hom.: 29 Cov.: 29 AF XY: 0.00576 AC XY: 4187 AN XY: 726804

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00497

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00468

Gnomad4 FIN exome AF: 0.00198

Gnomad4 NFE exome AF: 0.00648

Gnomad4 OTH exome AF: 0.00565

GnomAD4 genome AF: 0.00458 AC: 697 AN: 152292 Hom.: 2 Cov.: 34 AF XY: 0.00414 AC XY: 308 AN XY: 74478

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00794

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00663 Hom.: 5

Bravo AF: 0.00421

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00709 AC: 61

ExAC AF: 0.00476 AC: 578

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00845

EpiControl AF: 0.00759

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	FDXR: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

FDXR-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.0040
DANN	Benign	0.29
DEOGEN2	Benign	0.0020	.;.;.;.;T;.;T;T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.70	T;T;T;T;T;T;T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.0038	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.26	.;N;N;.;.;N;.;N
REVEL	Benign	0.016
Sift	Benign	0.85	.;T;T;.;.;T;.;T
Sift4G	Benign	0.90	T;T;T;T;T;T;T;T
Vest4		0.041
MVP		0.20
MPC		0.23
ClinPred		0.0036	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs35769464; hg19: chr17-72859001;