NM_001397406.1:c.1A>T

Variant names:

• chr19-10315996-T-A
• rs587777600
• NM_001397406.1:c.1A>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001397406.1(FDX2):​c.1A>T​(p.Met1?) variant causes a initiator codon 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 initiator_codon
• 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]

ENSG00000167807 (HGNC:):

RAVER1 (HGNC:30296): (ribonucleoprotein, PTB binding 1) Enables RNA binding activity. Predicted to be involved in regulation of alternative mRNA splicing, via spliceosome. Predicted to be located in cytoplasm. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 5 codons. Genomic position: 10315984. Lost 0.024 part of the original CDS.
• 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 rank	MANE	Protein	UniProt
FDX2	NM_001397406.1	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 5	ENST00000393708.3	NP_001384335.1
RAVER1	NM_133452.3	c.*1458A>T		downstream_gene_variant		ENST00000617231.5	NP_597709.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FDX2	ENST00000393708.3	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 5	1	NM_001397406.1	ENSP00000377311.5
ENSG00000167807	ENST00000452032.6	n.1A>T		non_coding_transcript_exon_variant	Exon 1 of 11	2		ENSP00000408510.3
ENSG00000267303	ENST00000586529.1	n.*1299+22A>T		intron_variant	Intron 6 of 7	5		ENSP00000467814.1
RAVER1	ENST00000617231.5	c.*1458A>T		downstream_gene_variant		5	NM_133452.3	ENSP00000482277.1

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

-

Laboratory Cellgenetics, GMDL Cellgenetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mitochondrial myopathy (PMID: 24281368). This variant is also known as c.1A>T. ClinVar contains an entry for this variant (Variation ID: 143059). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Inborn mitochondrial myopathy Uncertain:1

Jul 19, 2019

SIB Swiss Institute of Bioinformatics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

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
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;