19-10310578-C-T

Variant names:

• chr19-10310578-C-T
• NM_001397406.1:c.460G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001397406.1(FDX2):​c.460G>A​(p.Val154Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V154V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FDX2 NM_001397406.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.110
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000167807 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25741214).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001397406.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FDX2	NM_001397406.1	MANE Select	c.460G>A	p.Val154Met	missense	Exon 5 of 5	NP_001384335.1	Q6P4F2-1
	FDX2-ZGLP1	NR_176051.1		n.479G>A		non_coding_transcript_exon	Exon 5 of 8
	FDX2-ZGLP1	NR_176052.1		n.540G>A		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FDX2	ENST00000393708.3	TSL:1 MANE Select	c.460G>A	p.Val154Met	missense	Exon 5 of 5	ENSP00000377311.5	Q6P4F2-1
	ENSG00000167807	ENST00000452032.6	TSL:2	n.423G>A		non_coding_transcript_exon	Exon 5 of 11	ENSP00000408510.3	E7EQL1
	FDX2	ENST00000492239.5	TSL:2	c.55G>A	p.Val19Met	missense	Exon 4 of 4	ENSP00000488228.1	A0A0A0MTS8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Uncertain	0.98
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.11
PrimateAI	Benign	0.43	T
REVEL	Benign	0.030
Sift4G	Benign	0.091	T
Vest4		0.041
MVP		0.26
MPC		0.45
ClinPred		0.69	D
GERP RS		-4.7
Varity_R		0.031
gMVP		0.44
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

hg19: chr19-10421254;