rs200440128

Positions:

chr6-98926925-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.63

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 links:

FBXL4 (HGNC:):

FBXL4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 45 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-98926925-G-A is Pathogenic according to our data. Variant chr6-98926925-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-98926925-G-A is described in Lovd as [Pathogenic]. Variant chr6-98926925-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXL4	NM_001278716.2 linkuse as main transcript	c.64C>T	p.Arg22*	stop_gained	4/10	ENST00000369244.7	NP_001265645.1	Q9UKA2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXL4	ENST00000369244.7 linkuse as main transcript	c.64C>T	p.Arg22*	stop_gained	4/10	1	NM_001278716.2	ENSP00000358247.1		Q9UKA2
FBXL4	ENST00000229971.2 linkuse as main transcript	c.64C>T	p.Arg22*	stop_gained	3/9	1		ENSP00000229971.1		Q9UKA2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251138

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135726

show subpopulations

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 SAS exome

AF:

0.0000327

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.:

Cov.:

AF XY:

0.000177

AC XY:

129

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000210

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Jul 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 31, 2023	PM2_moderate, PM3, PVS1 -

Mitochondrial DNA depletion syndrome 13

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 27, 2014	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular and Human Genetics, Baylor College of Medicine	Apr 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	Jan 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Aug 10, 2017	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: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 Pathogenic. -

Neurodevelopmental delay

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

Vest4

0.43

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over