rs1011676

Variant names:

• chr6-98926524-G-A
• rs1011676
• NM_001278716.2:c.465C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.336
• Publications: 14 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: Benign. The variant received -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 VariationId is 260209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
FBXL4	NM_001278716.2	c.465C>T	p.Leu155Leu	synonymous_variant	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.465C>T	p.Leu155Leu	synonymous_variant	Exon 4 of 10	1	NM_001278716.2	ENSP00000358247.1
FBXL4	ENST00000229971.2	c.465C>T	p.Leu155Leu	synonymous_variant	Exon 3 of 9	1		ENSP00000229971.1

Frequencies

GnomAD3 genomes AF: 0.0540 AC: 8218 AN: 152108 Hom.: 333 Cov.: 32

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

GnomAD2 exomes AF: 0.0595 AC: 14914 AN: 250634 AF XY: 0.0626

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 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.: 32 AF XY: 0.0742 AC XY: 53918 AN XY: 726774

African (AFR) AF: 0.0120 AC: 401 AN: 33474

American (AMR) AF: 0.0343 AC: 1534 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0653 AC: 1702 AN: 26072

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39692

South Asian (SAS) AF: 0.0692 AC: 5959 AN: 86114

European-Finnish (FIN) AF: 0.0648 AC: 3459 AN: 53406

Middle Eastern (MID) AF: 0.0632 AC: 364 AN: 5764

European-Non Finnish (NFE) AF: 0.0813 AC: 90371 AN: 1111598

Other (OTH) AF: 0.0643 AC: 3883 AN: 60376

GnomAD4 genome AF: 0.0540 AC: 8218 AN: 152226 Hom.: 333 Cov.: 32 AF XY: 0.0539 AC XY: 4013 AN XY: 74430

African (AFR) AF: 0.0134 AC: 555 AN: 41546

American (AMR) AF: 0.0464 AC: 709 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0611 AC: 212 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5176

South Asian (SAS) AF: 0.0676 AC: 326 AN: 4824

European-Finnish (FIN) AF: 0.0618 AC: 655 AN: 10602

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0818 AC: 5564 AN: 68002

Other (OTH) AF: 0.0540 AC: 114 AN: 2112

Alfa AF: 0.0685 Hom.: 958

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

Submissions by phenotype

not specified Benign:2

Dec 02, 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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 26, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

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.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
PhyloP100		0.34
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1011676; hg19: chr6-99374400;