chr6-98875677-TTTTTT-ATTTTTC

Variant names:

• chr6-98875677-TTTTTT-ATTTTTC
• rs879255542
• NM_001278716.2:c.1435_1440delAAAAAAinsGAAAAAT

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2 PP2 PP5_Moderate

The NM_012160.5(FBXL4):​c.1435_1440delAAAAAAinsGAAAAAT​(p.Lys479GlufsTer12) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXL4 NM_012160.5 frameshift, missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.48
• 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: Pathogenic. The variant received 13 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.55467 (below the threshold of 3.09). Trascript score misZ: 1.2845 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, mitochondrial DNA depletion syndrome 13.
• PP5: Variant 6-98875677-TTTTTT-ATTTTTC is Pathogenic according to our data. Variant chr6-98875677-TTTTTT-ATTTTTC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2501198.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1435_1440delAAAAAAinsGAAAAAT	p.Lys479GlufsTer12	frameshift missense	Exon 9 of 10	NP_001265645.1
	FBXL4	NM_012160.5		c.1435_1440delAAAAAAinsGAAAAAT	p.Lys479GlufsTer12	frameshift missense	Exon 8 of 9	NP_036292.2
	FBXL4	NR_103836.2		n.1420_1425delAAAAAAinsGAAAAAT		non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL4	ENST00000369244.7	TSL:1 MANE Select	c.1435_1440delAAAAAAinsGAAAAAT	p.Lys479GlufsTer12	frameshift missense	Exon 9 of 10	ENSP00000358247.1
	FBXL4	ENST00000229971.2	TSL:1	c.1435_1440delAAAAAAinsGAAAAAT	p.Lys479GlufsTer12	frameshift missense	Exon 8 of 9	ENSP00000229971.1
	FBXL4	ENST00000892543.1		c.1456_1461delAAAAAAinsGAAAAAT	p.Lys486GlufsTer12	frameshift missense	Exon 9 of 10	ENSP00000562602.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Leigh syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs879255542; hg19: chr6-99323553;