Genetic Variant FDX2:p.Met1? (chr19-10315996-T-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_001397406.1(FDX2):c.1A>C(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 0.00000069 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
NM_001397406.1 initiator_codon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.68

Publications

1 publications found

Variant links:

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 links:

ENSG00000167807 (HGNC:):

ENSG00000167807 links:

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]

RAVER1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 2 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;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FDX2	NM_001397406.1	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 5	NP_001384335.1
FDX2-ZGLP1	NR_176051.1		n.20A>C		non_coding_transcript_exon	Exon 1 of 8
FDX2-ZGLP1	NR_176052.1		n.20A>C		non_coding_transcript_exon	Exon 1 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FDX2	ENST00000393708.3	TSL:1 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 5	ENSP00000377311.5
ENSG00000167807	ENST00000452032.6	TSL:2	n.1A>C		non_coding_transcript_exon	Exon 1 of 11	ENSP00000408510.3
ENSG00000267303	ENST00000586529.1	TSL:5	n.*1299+22A>C		intron	N/A	ENSP00000467814.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1450224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721674

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32720

American (AMR)

AF:

0.00

AC:

AN:

40392

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25692

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

84698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1109138

Other (OTH)

AF:

0.00

AC:

AN:

59912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Benign

(source)

DANN

Benign

0.92

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.38

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.90

MetaSVM

Benign

-0.32

PhyloP100

2.7

REVEL

Uncertain

0.63

Sift4G

Benign

0.081

Vest4

0.88

MVP

0.24

ClinPred

1.0

GERP RS

4.8

PromoterAI

-0.78

Under-expression

(source)

Varity_R

0.52

gMVP

0.50

Mutation Taster

=40/160

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over