6-98917383-T-C

Variant names:

• chr6-98917383-T-C
• rs748199266
• NM_001278716.2:c.849A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_012160.5(FBXL4):​c.849A>G​(p.Leu283Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L283L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBXL4 NM_012160.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.129
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=0.129 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012160.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL4	NM_001278716.2	MANE Select	c.849A>G	p.Leu283Leu	synonymous	Exon 5 of 10	NP_001265645.1
	FBXL4	NM_012160.5		c.849A>G	p.Leu283Leu	synonymous	Exon 4 of 9	NP_036292.2
	FBXL4	NR_103836.2		n.843+9094A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL4	ENST00000369244.7	TSL:1 MANE Select	c.849A>G	p.Leu283Leu	synonymous	Exon 5 of 10	ENSP00000358247.1
	FBXL4	ENST00000229971.2	TSL:1	c.849A>G	p.Leu283Leu	synonymous	Exon 4 of 9	ENSP00000229971.1
	FBXL4	ENST00000892543.1		c.870A>G	p.Leu290Leu	synonymous	Exon 5 of 10	ENSP00000562602.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448610 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719288

African (AFR) AF: 0.00 AC: 0 AN: 33114

American (AMR) AF: 0.00 AC: 0 AN: 43454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 83906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105098

Other (OTH) AF: 0.0000167 AC: 1 AN: 59798

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.4
DANN	Benign	0.74
PhyloP100		0.13
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs748199266; hg19: chr6-99365259;