19-10310591-C-T

Variant names:

• chr19-10310591-C-T
• rs760324760
• NM_001397406.1:c.447G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM2 PP3_Strong BP7

The NM_001397406.1(FDX2):​c.447G>A​(p.Leu149Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L149L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FDX2 NM_001397406.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_noAF computational evidence supports a deleterious effect, 0.56
• BP7: Synonymous conserved (PhyloP=1.26 with no splicing effect.

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.447G>A	p.Leu149Leu	synonymous	Exon 5 of 5	NP_001384335.1	Q6P4F2-1
	FDX2-ZGLP1	NR_176051.1		n.466G>A		non_coding_transcript_exon	Exon 5 of 8
	FDX2-ZGLP1	NR_176052.1		n.527G>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.447G>A	p.Leu149Leu	synonymous	Exon 5 of 5	ENSP00000377311.5	Q6P4F2-1
	ENSG00000167807	ENST00000452032.6	TSL:2	n.410G>A		non_coding_transcript_exon	Exon 5 of 11	ENSP00000408510.3	E7EQL1
	FDX2	ENST00000492239.5	TSL:2	c.42G>A	p.Leu14Leu	synonymous	Exon 4 of 4	ENSP00000488228.1	A0A0A0MTS8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.56
CADD	Benign	6.2
DANN	Uncertain	0.98
PhyloP100		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

dbSNP: rs760324760; hg19: chr19-10421267;