rs1011676

Positions:

chr6-98926524-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001278716.2(FBXL4):c.465C>T(p.Leu155Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0718 in 1,613,406 control chromosomes in the GnomAD database, including 4,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.054 ( 333 hom., cov: 32)

Exomes 𝑓: 0.074 ( 4484 hom. )

Consequence

FBXL4
NM_001278716.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.336

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 6-98926524-G-A is Benign according to our data. Variant chr6-98926524-G-A is described in ClinVar as [Benign]. Clinvar id is 260209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-98926524-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.336 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.08 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXL4	NM_001278716.2 linkuse as main transcript	c.465C>T	p.Leu155Leu	synonymous_variant	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.465C>T	p.Leu155Leu	synonymous_variant	4/10	1	NM_001278716.2	ENSP00000358247.1		Q9UKA2
FBXL4	ENST00000229971.2 linkuse as main transcript	c.465C>T	p.Leu155Leu	synonymous_variant	3/9	1		ENSP00000229971.1		Q9UKA2

Frequencies

GnomAD3 genomes

AF:

0.0540

AC:

8218

AN:

152108

Hom.:

333

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0134

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0464

Gnomad ASJ

AF:

0.0611

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.0677

Gnomad FIN

AF:

0.0618

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0818

Gnomad OTH

AF:

0.0545

GnomAD3 exomes

AF:

0.0595

AC:

14914

AN:

250634

Hom.:

574

AF XY:

0.0626

AC XY:

8473

AN XY:

135424

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.0329

Gnomad ASJ exome

AF:

0.0626

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.0665

Gnomad FIN exome

AF:

0.0618

Gnomad NFE exome

AF:

0.0804

Gnomad OTH exome

AF:

0.0746

GnomAD4 exome

AF:

0.0737

AC:

107688

AN:

1461180

Hom.:

4484

Cov.:

AF XY:

0.0742

AC XY:

53918

AN XY:

726774

show subpopulations

Gnomad4 AFR exome

AF:

0.0120

Gnomad4 AMR exome

AF:

0.0343

Gnomad4 ASJ exome

AF:

0.0653

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.0692

Gnomad4 FIN exome

AF:

0.0648

Gnomad4 NFE exome

AF:

0.0813

Gnomad4 OTH exome

AF:

0.0643

GnomAD4 genome

AF:

0.0540

AC:

8218

AN:

152226

Hom.:

333

Cov.:

AF XY:

0.0539

AC XY:

4013

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0134

Gnomad4 AMR

AF:

0.0464

Gnomad4 ASJ

AF:

0.0611

Gnomad4 EAS

AF:

0.00193

Gnomad4 SAS

AF:

0.0676

Gnomad4 FIN

AF:

0.0618

Gnomad4 NFE

AF:

0.0818

Gnomad4 OTH

AF:

0.0540

Alfa

AF:

0.0734

Hom.:

772

Bravo

AF:

0.0498

Asia WGS

AF:

0.0340

AC:

119

AN:

3478

EpiCase

AF:

0.0819

EpiControl

AF:

0.0771

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2016	- -

Mitochondrial DNA depletion syndrome 13

Benign:1

Benign, criteria provided, single submitter

reference population

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

Aug 10, 2017

The NM_012160.4:c.465C>T (NP_036292.2:p.Leu155=) [GRCH38: NC_000006.12:g.98926524G>A] 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

-0.49

CADD

Benign

2.2

DANN

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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