19-10310517-T-A

Position:

• chr19-10310517-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000393708.3(FDX2):​c.521A>T​(p.Tyr174Phe) variant causes a missense change. 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 ENST00000393708.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.12

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 Uncertain_significance. Variant got 2 ACMG points.

• 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.521A>T	p.Tyr174Phe	missense_variant	5/5	ENST00000393708.3	NP_001384335.1
FDX2-ZGLP1	NR_176051.1	n.540A>T		non_coding_transcript_exon_variant	5/8
FDX2-ZGLP1	NR_176052.1	n.601A>T		non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FDX2	ENST00000393708.3	c.521A>T	p.Tyr174Phe	missense_variant	5/5	1	NM_001397406.1	ENSP00000377311	P1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 10, 2022

This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 177 of the FDX2 protein (p.Tyr177Phe). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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	Benign	0.27
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	0.98
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Uncertain	-0.12	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
REVEL	Benign	0.28
Sift4G	Benign	0.11	T;T;T
Vest4		0.53
MVP		0.37
MPC		0.70
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.25
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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: chr19-10421193;