19-10315996-T-G

Position:

• chr19-10315996-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The ENST00000393708.3(FDX2):​c.1A>C​(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 0.00000069 in 1,450,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FDX2 ENST00000393708.3 start_lost
• Clinical Significance: Not reported in ClinVar
• 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 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000393708.3 (FDX2) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 143059
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FDX2	NM_001397406.1	c.1A>C	p.Met1?	start_lost	1/5	ENST00000393708.3	NP_001384335.1
FDX2-ZGLP1	NR_176051.1	n.20A>C		non_coding_transcript_exon_variant	1/8
FDX2-ZGLP1	NR_176052.1	n.20A>C		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>C	p.Met1?	start_lost	1/5	1	NM_001397406.1	ENSP00000377311	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450224 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

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	20
DANN	Benign	0.92
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.80	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
Varity_R		0.52
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;