rs200440128

Variant names:

• chr6-98926925-G-A
• rs200440128
• NM_001278716.2:c.64C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001278716.2(FBXL4):​c.64C>T​(p.Arg22*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: FBXL4 NM_001278716.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.63
• Publications: 7 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 83 pathogenic variants in the truncated region.
• PP5: Variant 6-98926925-G-A is Pathogenic according to our data. Variant chr6-98926925-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 209153.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	c.64C>T	p.Arg22*	stop_gained	Exon 4 of 10	ENST00000369244.7	NP_001265645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL4	ENST00000369244.7	c.64C>T	p.Arg22*	stop_gained	Exon 4 of 10	1	NM_001278716.2	ENSP00000358247.1
FBXL4	ENST00000229971.2	c.64C>T	p.Arg22*	stop_gained	Exon 3 of 9	1		ENSP00000229971.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152080 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000597 AC: 15 AN: 251138 AF XY: 0.0000663

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000174 AC: 254 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.000177 AC XY: 129 AN XY: 727216

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000210 AC: 234 AN: 1111982

Other (OTH) AF: 0.000149 AC: 9 AN: 60392

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152080 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74274

African (AFR) AF: 0.0000242 AC: 1 AN: 41398

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Jul 27, 2017

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 02, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27290639, 27743463, 28940506, 26633545, 30804983, 32525278, 33726816) -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg22*) in the FBXL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBXL4 are known to be pathogenic (PMID: 23993193, 23993194, 25868664). This variant is present in population databases (rs200440128, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with clinical features of FBXL4-related conditions (PMID: 27290639, 27743463). ClinVar contains an entry for this variant (Variation ID: 209153). For these reasons, this variant has been classified as Pathogenic. -

Jul 31, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_moderate, PM3, PVS1 -

Mitochondrial DNA depletion syndrome 13 Pathogenic:5

Apr 16, 2020

Department of Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 28, 2021

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2014

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory homozygous in a 32-year-old male with intellectual disability, hypotonia, dragging of right foot when walking, tremors, dysmorphisms, hyperextensibility, failure to thrive, amblyopia, myopia, mitral valve prolapse, scoliosis, serial episodes of lactic acidosis, white matter abnormalities. Variant pathogenic in recessive state; heterozygotes are carriers. -

Aug 10, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_012160.4:c.64C>T (NP_036292.2:p.Arg22Ter) [GRCH38: NC_000006.12:g.98926925G>A] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:27743463 ; 27290639 . This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PVS1:This variant is a predcted null variant in FBXL4 where loss of function is a known mechanism of disease. 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. PP4:Patient’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 Pathogenic. -

Mar 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodevelopmental delay Pathogenic:1

-

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

May 13, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.64C>T (p.R22*) alteration, located in exon 3 (coding exon 1) of the FBXL4 gene, consists of a C to T substitution at nucleotide position 64. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 22. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.006% (16/282522) total alleles studied. The highest observed frequency was 0.009% (12/128900) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other FBXL4 variants in individuals with features consistent with FBXL4-related mitochondrial DNA depletion syndrome; in at least one instance, the variants were identified in trans (Pronicka, 2016; Dai, 2016; Ambry internal data). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.6
Vest4		0.43
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=8/192	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs200440128; hg19: chr6-99374801; COSMIC: COSV57745099;