19-10310616-G-A

Variant names:

• chr19-10310616-G-A
• rs888630930
• NM_001397406.1:c.422C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001397406.1(FDX2):​c.422C>T​(p.Pro141Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FDX2 NM_001397406.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.87

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-10310616-G-A is Pathogenic according to our data. Variant chr19-10310616-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 623644.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FDX2	NM_001397406.1	c.422C>T	p.Pro141Leu	missense_variant	Exon 5 of 5	ENST00000393708.3	NP_001384335.1
FDX2-ZGLP1	NR_176051.1	n.441C>T		non_coding_transcript_exon_variant	Exon 5 of 8
FDX2-ZGLP1	NR_176052.1	n.502C>T		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FDX2	ENST00000393708.3	c.422C>T	p.Pro141Leu	missense_variant	Exon 5 of 5	1	NM_001397406.1	ENSP00000377311.5
ENSG00000167807	ENST00000452032.6	n.396-11C>T		intron_variant	Intron 4 of 10	2		ENSP00000408510.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn mitochondrial myopathy Pathogenic:2

Mar 25, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 19, 2019

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Likely pathogenic for Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PS3-Moderate, PP1-Strong. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.65	T
PrimateAI	Uncertain	0.65	T
REVEL	Uncertain	0.47
Sift4G	Benign	0.71	T;T;T
Vest4		0.59
MVP		0.71
MPC		1.0
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.63
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs888630930; hg19: chr19-10421292; COSMIC: COSV100593729; COSMIC: COSV100593729;