rs587777600

Positions:

• chr19-10315996-T-A
• chr19-10315996-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001397406.1(FDX2):​c.1A>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,450,224 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: FDX2 NM_001397406.1 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 2.68

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-ZGLP1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-10315996-T-A is Pathogenic according to our data. Variant chr19-10315996-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143059.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}. Variant chr19-10315996-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FDX2	NM_001397406.1	c.1A>T	p.Met1?	start_lost	1/5	ENST00000393708.3	NP_001384335.1
FDX2-ZGLP1	NR_176051.1	n.20A>T		non_coding_transcript_exon_variant	1/8
FDX2-ZGLP1	NR_176052.1	n.20A>T		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FDX2	ENST00000393708.3	c.1A>T	p.Met1?	start_lost	1/5	1	NM_001397406.1	ENSP00000377311	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000621 AC: 9 AN: 1450224 Hom.: 0 Cov.: 35 AF XY: 0.00000970 AC XY: 7 AN XY: 721674

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000811

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory Cellgenetics, GMDL Cellgenetics

-

- -

Mitochondrial myopathy, episodic, without optic atrophy and reversible leukoencephalopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2014

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2022

This missense change has been observed in individual(s) with mitochondrial myopathy (PMID: 24281368). 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. 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: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 143059). This variant is also known as c.1A>T. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4 of the FDX2 protein (p.Met4Leu). -

Inborn mitochondrial myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

Jul 19, 2019

This variant is interpreted as a variant of uncertain significance for Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PS3-Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	21
DANN	Benign	0.91
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.32	T
MutationTaster	Benign	1.0	D;N
REVEL	Uncertain	0.63
Sift4G	Benign	0.081	T
Vest4		0.88
MVP		0.24
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.52
gMVP		0.50

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: rs587777600; hg19: chr19-10426672;