19-10310519-G-C

Variant names:

• chr19-10310519-G-C
• NM_001397406.1:c.519C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001397406.1(FDX2):​c.519C>G​(p.Phe173Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FDX2 NM_001397406.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FDX2	NM_001397406.1	c.519C>G	p.Phe173Leu	missense_variant	Exon 5 of 5	ENST00000393708.3	NP_001384335.1
FDX2-ZGLP1	NR_176051.1	n.538C>G		non_coding_transcript_exon_variant	Exon 5 of 8
FDX2-ZGLP1	NR_176052.1	n.599C>G		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.519C>G	p.Phe173Leu	missense_variant	Exon 5 of 5	1	NM_001397406.1	ENSP00000377311.5
ENSG00000167807	ENST00000452032.6	n.*53C>G		non_coding_transcript_exon_variant	Exon 5 of 11	2		ENSP00000408510.3
ENSG00000167807	ENST00000452032.6	n.*53C>G		3_prime_UTR_variant	Exon 5 of 11	2		ENSP00000408510.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 176 of the FDX2 protein (p.Phe176Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FDX2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1370974). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;.;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.61	T
PrimateAI	Pathogenic	0.81	D
REVEL	Benign	0.22
Sift4G	Uncertain	0.0080	D;T;T
Vest4		0.70
MVP		0.46
MPC		0.93
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.41
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-10421195; COSMIC: COSV100593814; COSMIC: COSV100593814;