rs398123061

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PP2PP5_Very_Strong

The NM_001278716.2(FBXL4):c.1444C>T(p.Arg482Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R482Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

FBXL4
NM_001278716.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 3.43

Publications

11 publications found

Variant links:

Genes affected

FBXL4 (HGNC:13601): (F-box and leucine rich repeat protein 4) This gene encodes a member of the F-box protein family, which are characterized by an approximately 40 amino acid motif, the F-box. F-box proteins constitute one subunit of modular E3 ubiquitin ligase complexes, called SCF complexes, which function in phosphorylation-dependent ubiquitination. The F-box domain mediates protein-protein interactions and binds directly to S-phase kinase-associated protein 1. In addition to an F-box domain, the encoded protein contains at least 9 tandem leucine-rich repeats. The ubiquitin ligase complex containing the encoded protein may function in cell-cycle control by regulating levels of lysine-specific demethylase 4A. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

FBXL4 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial DNA depletion syndrome 13
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

FBXL4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001278716.2

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.55467 (below the threshold of 3.09). Trascript score misZ: 1.2845 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, mitochondrial DNA depletion syndrome 13.

PP5

Variant 6-98875673-G-A is Pathogenic according to our data. Variant chr6-98875673-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 66093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL4	NM_001278716.2 link	c.1444C>T	p.Arg482Trp	missense_variant	Exon 9 of 10	ENST00000369244.7	NP_001265645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL4	ENST00000369244.7 link	c.1444C>T	p.Arg482Trp	missense_variant	Exon 9 of 10	1	NM_001278716.2	ENSP00000358247.1
FBXL4	ENST00000229971.2 link	c.1444C>T	p.Arg482Trp	missense_variant	Exon 8 of 9	1		ENSP00000229971.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000280

AC:

AN:

249754

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461536

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.0000447

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111954

Other (OTH)

AF:

0.0000166

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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

AF:

0.0000329

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000238

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 13

Pathogenic:5

Oct 04, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2017

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NM_012160.4:c.1444C>T (NP_036292.2:p.Arg482Trp) [GRCH38: NC_000006.12:g.98875673G>A] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:23993194 ; 25868664 ; 27743463 . This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 13 which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 13 in multiple affected family members. PP2:This is a missense variant in FBXL4 with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on FBXL4 structure, function, or protein-protein interaction. PP4:Patientâ€™s phenotype or family history is highly specific for FBXL4. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Likely Pathogenic. -

Sep 05, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 23, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) (MIM#615471). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected individuals carrying the same variant have been reported to display clinical variability (PMID: 30804983). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 8 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.R482Q: 111 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated leucine-rich repeat region 5 (PMID: 28940506; Uniprot). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.R482Q variant has been classified as variant of uncertain significance (LOVD; PMID: 28940506). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in two individuals with early-onset mitochondrial encephalomyopathy and mitochondrial maintenance defect, respectively, and has been reported as either likely pathogenic or pathogenic by clinical diagnostic laboratories (ClinVar; PMIDs: 23993194, 25868664). (SP) 0906 - Segregation evidence for this variant is inconclusive. There is insufficient information to determine segregation of this variant (PMID: 23993194). (I) 1010 - Functional evidence for this variant is inconclusive. Fibroblasts from a homozygous carrier of this variant demonstrated reduced mitochondrial DNA amount compared to the mean value of controls; however, the standard deviation was within with the control range (PMID: 23993194). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:5

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 482 of the FBXL4 protein (p.Arg482Trp). This variant is present in population databases (rs398123061, gnomAD 0.005%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 23993194, 25868664, 27743463). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66093). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBXL4 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Aug 01, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in homozygous state in patients with features consistent with FBXL4-related mitochondrial DNA depletion syndrome and not observed in homozygous state in controls (PMID: 23993194, 37377599); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27182039, 23993194, 27743463, 37377599, 34052969, 37644014) -

Leigh syndrome

Pathogenic:1

Jul 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FBXL4 c.1444C>T (p.Arg482Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249996 control chromosomes (gnomAD and publication data). c.1444C>T has been reported in the literature in multiple individuals affected with Early-Onset Mitochondrial Encephalomyopathy, including homozygotes (Gai_2013, Alazami_2014, Huemer_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25558065, 23993194, 25868664). ClinVar contains an entry for this variant (Variation ID: 66093). Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Mar 15, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1444C>T (p.R482W) alteration is located in exon 8 (coding exon 6) of the FBXL4 gene. This alteration results from a C to T substitution at nucleotide position 1444, causing the arginine (R) at amino acid position 482 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (8/281146) total alleles studied. The highest observed frequency was 0.01% (2/19936) of East Asian alleles. This variant has been reported as homozygous in three siblings and one unrelated individual with features consistent with FBXL4-related mitochondrial DNA depletion syndrome (Gai, 2013; Forny, 2021). In addition, this variant has been reported compound heterozygous with other FBXL4 variants in multiple affected individuals (Dai, 2016; Martin-Saavedra, 2022). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Mitochondrial encephalomyopathy;C0557874:Global developmental delay

Pathogenic:1

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

.;D

M_CAP

Benign

0.073

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.1

M;M

PhyloP100

3.4

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.25

Sift

Benign

0.044

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;D

Vest4

0.63

MutPred

0.49

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

0.63

MPC

0.31

ClinPred

0.96

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.21

gMVP

0.66

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over