rs878853112

Variant names:

• chr6-98875553-TGCTGCTCTGCAGAGTTGG-T
• rs878853112
• NM_001278716.2:c.1546_1563delCCAACTCTGCAGAGCAGC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM4 PP3 PP5_Very_Strong

The NM_001278716.2(FBXL4):​c.1546_1563delCCAACTCTGCAGAGCAGC​(p.Pro516_Ser521del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXL4 NM_001278716.2 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.60
• Publications: 1 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 disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome 13

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001278716.2.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 6-98875553-TGCTGCTCTGCAGAGTTGG-T is Pathogenic according to our data. Variant chr6-98875553-TGCTGCTCTGCAGAGTTGG-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 235778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL4	NM_001278716.2	MANE Select	c.1546_1563delCCAACTCTGCAGAGCAGC	p.Pro516_Ser521del	conservative_inframe_deletion	Exon 9 of 10	NP_001265645.1	Q9UKA2
	FBXL4	NM_012160.5		c.1546_1563delCCAACTCTGCAGAGCAGC	p.Pro516_Ser521del	conservative_inframe_deletion	Exon 8 of 9	NP_036292.2
	FBXL4	NR_103836.2		n.1531_1548delCCAACTCTGCAGAGCAGC		non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL4	ENST00000369244.7	TSL:1 MANE Select	c.1546_1563delCCAACTCTGCAGAGCAGC	p.Pro516_Ser521del	conservative_inframe_deletion	Exon 9 of 10	ENSP00000358247.1	Q9UKA2
	FBXL4	ENST00000229971.2	TSL:1	c.1546_1563delCCAACTCTGCAGAGCAGC	p.Pro516_Ser521del	conservative_inframe_deletion	Exon 8 of 9	ENSP00000229971.1	Q9UKA2
	FBXL4	ENST00000892543.1		c.1567_1584delCCAACTCTGCAGAGCAGC	p.Pro523_Ser528del	conservative_inframe_deletion	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

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial DNA depletion syndrome 13 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=9/191	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs878853112; hg19: chr6-99323429;