6-98927004-G-C

Variant names:

• chr6-98927004-G-C
• rs752104950
• NM_001278716.2:c.-16C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001278716.2(FBXL4):​c.-16C>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000687 in 1,455,344 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FBXL4 NM_001278716.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.80
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278716.2. 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.-16C>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 10	NP_001265645.1
	FBXL4	NM_001278716.2	MANE Select	c.-16C>G		5_prime_UTR	Exon 4 of 10	NP_001265645.1
	FBXL4	NM_012160.5		c.-16C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	NP_036292.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL4	ENST00000369244.7	TSL:1 MANE Select	c.-16C>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 10	ENSP00000358247.1
	FBXL4	ENST00000229971.2	TSL:1	c.-16C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	ENSP00000229971.1
	FBXL4	ENST00000369244.7	TSL:1 MANE Select	c.-16C>G		5_prime_UTR	Exon 4 of 10	ENSP00000358247.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455344 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722926

African (AFR) AF: 0.00 AC: 0 AN: 33228

American (AMR) AF: 0.00 AC: 0 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25914

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.00 AC: 0 AN: 85752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107666

Other (OTH) AF: 0.00 AC: 0 AN: 60086

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.92
PhyloP100		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs752104950; hg19: chr6-99374880;