Variant 19-10310595-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001397406.1(FDX2):c.443G>A(p.Arg148Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R148W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

FDX2
NM_001397406.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.02

Variant links:

Genes affected

FDX2 (HGNC:30546): (ferredoxin 2) This gene encodes a member of the ferredoxin family. The encoded protein contains a 2Fe-2S ferredoxin-type domain and is essential for heme A and Fe/S protein biosynthesis. Mutation in FDX1L gene is associated with mitochondrial muscle myopathy. [provided by RefSeq, Sep 2014]

FDX2 links:

FDX2-ZGLP1 (HGNC:):

FDX2-ZGLP1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FDX2	NM_001397406.1 linkuse as main transcript	c.443G>A	p.Arg148Gln	missense_variant	5/5	ENST00000393708.3
FDX2-ZGLP1	NR_176051.1 linkuse as main transcript	n.462G>A		non_coding_transcript_exon_variant	5/8
FDX2-ZGLP1	NR_176052.1 linkuse as main transcript	n.523G>A		non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FDX2	ENST00000393708.3 linkuse as main transcript	c.443G>A	p.Arg148Gln	missense_variant	5/5	1	NM_001397406.1	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251042

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 151 of the FDX2 protein (p.Arg151Gln). This variant is present in population databases (rs765480349, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FDX2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C35"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.46

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.82

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;.;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Pathogenic

0.83

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.66

REVEL

Uncertain

0.60

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.94

MVP

0.66

MPC

1.3

ClinPred

1.0

GERP RS

4.3

Varity_R

0.55

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over