6-98875548-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001278716.2(FBXL4):c.1569G>A(p.Gly523Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,614,018 control chromosomes in the GnomAD database, including 3,800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 355 hom., cov: 32)

Exomes 𝑓: 0.066 ( 3445 hom. )

Consequence

FBXL4
NM_001278716.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.927

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 6-98875548-C-T is Benign according to our data. Variant chr6-98875548-C-T is described in ClinVar as [Benign]. Clinvar id is 260208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-98875548-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.927 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL4	NM_001278716.2 link	c.1569G>A	p.Gly523Gly	synonymous_variant	Exon 9 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.1569G>A	p.Gly523Gly	synonymous_variant	Exon 9 of 10	1	NM_001278716.2	ENSP00000358247.1		Q9UKA2
FBXL4	ENST00000229971.2 link	c.1569G>A	p.Gly523Gly	synonymous_variant	Exon 8 of 9	1		ENSP00000229971.1		Q9UKA2

Frequencies

GnomAD3 genomes

AF:

0.0658

AC:

10011

AN:

152078

Hom.:

354

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0701

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0459

Gnomad ASJ

AF:

0.0948

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0479

Gnomad FIN

AF:

0.0634

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0730

Gnomad OTH

AF:

0.0712

GnomAD3 exomes

AF:

0.0566

AC:

14210

AN:

251030

Hom.:

508

AF XY:

0.0568

AC XY:

7699

AN XY:

135652

show subpopulations

Gnomad AFR exome

AF:

0.0688

Gnomad AMR exome

AF:

0.0302

Gnomad ASJ exome

AF:

0.0975

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0479

Gnomad FIN exome

AF:

0.0610

Gnomad NFE exome

AF:

0.0694

Gnomad OTH exome

AF:

0.0660

GnomAD4 exome

AF:

0.0664

AC:

96995

AN:

1461822

Hom.:

3445

Cov.:

AF XY:

0.0654

AC XY:

47566

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0698

Gnomad4 AMR exome

AF:

0.0321

Gnomad4 ASJ exome

AF:

0.0968

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0479

Gnomad4 FIN exome

AF:

0.0636

Gnomad4 NFE exome

AF:

0.0707

Gnomad4 OTH exome

AF:

0.0684

GnomAD4 genome

AF:

0.0658

AC:

10017

AN:

152196

Hom.:

355

Cov.:

AF XY:

0.0655

AC XY:

4877

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0700

Gnomad4 AMR

AF:

0.0459

Gnomad4 ASJ

AF:

0.0948

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0483

Gnomad4 FIN

AF:

0.0634

Gnomad4 NFE

AF:

0.0730

Gnomad4 OTH

AF:

0.0710

Alfa

AF:

0.0655

Hom.:

381

Bravo

AF:

0.0645

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.0690

EpiControl

AF:

0.0685

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 04, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Feb 15, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial DNA depletion syndrome 13

Benign:1

Aug 10, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: reference population

The NM_012160.4:c.1569G>A (NP_036292.2:p.Gly523=) [GRCH38: NC_000006.12:g.98875548C>T] variant in FBXL4 gene is interpretated to be a Benign - Stand Alone based on ACMG guidelines (PMID: 25741868). This variant meets one or more of the following evidence codes reported in the ACMG-guideline. BA1:Minor allele frequency is too high for the Mitochondrial DNA depletion syndrome 13. BS2:Observation of the variant is in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 13. 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 Benign - Stand Alone. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

1.4

DANN

Benign

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

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