rs372544390

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2BP4BP6

The NM_001278716.2(FBXL4):c.1073G>A(p.Arg358Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

FBXL4
NM_001278716.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.57

Publications

2 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: Likely_benign. The variant received -1 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.3263287).

BP6

Variant 6-98905456-C-T is Benign according to our data. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684. Variant chr6-98905456-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437684.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL4	NM_001278716.2 link	c.1073G>A	p.Arg358Lys	missense_variant	Exon 6 of 10	ENST00000369244.7	NP_001265645.1	Q9UKA2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL4	ENST00000369244.7 link	c.1073G>A	p.Arg358Lys	missense_variant	Exon 6 of 10	1	NM_001278716.2	ENSP00000358247.1		Q9UKA2
FBXL4	ENST00000229971.2 link	c.1073G>A	p.Arg358Lys	missense_variant	Exon 5 of 9	1		ENSP00000229971.1		Q9UKA2

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.000353

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000131

AC:

AN:

251370

AF XY:

0.000140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000248

AC:

363

AN:

1461764

Hom.:

Cov.:

AF XY:

0.000223

AC XY:

162

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33470

American (AMR)

AF:

0.000112

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000311

AC:

346

AN:

1111928

Other (OTH)

AF:

0.000149

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000204

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.000229

Hom.:

Bravo

AF:

0.000189

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Oct 10, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4 -

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitochondrial DNA depletion syndrome 13

Uncertain:1

Aug 10, 2017

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:reference population

The NM_012160.4:c.1073G>A (NP_036292.2:p.Arg358Lys) [GRCH38: NC_000006.12:g.98905456C>T] variant in FBXL4 gene is interpretated to be a Uncertain Significance - Conflicting Evidence based on ACMG guidelines (PMID: 25741868). 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. BP4:Computational evidence/predictors indicate no impact on the FBXL4 structure, function, or protein-protein interaction. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Uncertain Significance - Conflicting Evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.031

T;T

Eigen

Benign

-0.11

Eigen_PC

Benign

0.083

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

.;T

M_CAP

Benign

0.0088

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

L;L

PhyloP100

7.6

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.16

N;N

REVEL

Benign

0.11

Sift

Benign

0.79

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.75

MVP

0.43

MPC

0.065

ClinPred

0.078

GERP RS

4.6

Varity_R

0.32

gMVP

0.60

Mutation Taster

=87/13

polymorphism

(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