rs1554219474

chr6-98905461-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001278716.2(FBXL4):c.1067del(p.Gly356AlafsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FBXL4 NM_001278716.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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
• PP5: Variant 6-98905461-GC-G is Pathogenic according to our data. Variant chr6-98905461-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 437498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-98905461-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXL4	NM_001278716.2	c.1067del	p.Gly356AlafsTer15	frameshift_variant	6/10	ENST00000369244.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXL4	ENST00000369244.7	c.1067del	p.Gly356AlafsTer15	frameshift_variant	6/10	1	NM_001278716.2	P1
FBXL4	ENST00000229971.2	c.1067del	p.Gly356AlafsTer15	frameshift_variant	5/9	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461760 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome 13 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Aug 10, 2017	The NM_012160.4:c.1067del (NP_036292.2:p.Gly356AlafsTer15) [GRCH38: NC_000006.12:g.98905463del] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:23993194 ; 25868664 . This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PVS1:This variant is a predcted null variant in FBXL4 where loss of function is a known mechanism of disease. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 13 which is a recessive disorder. PP4:Patient’s phenotype or family history is highly specific for FBXL4. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously reported as disease-causing and was found twice in our laboratory: once in trans with another pathogenic variant in an 8-year-old female with primary mitochondrial respiratory chain disease; once homozygous in a 3-year-old male with regression, severe failure to thrive, hypotonia, microcephaly, severe lactic acidosis, nystagmus, mild dysmorphisms, and 3 siblings who died in infancy -

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2018	The c.1067delG variant has been reported previously in the homozygous and compound heterozygous states in patients with symptoms that include early-onset lactic acidemia, hypotonia, encephalopathy, developmental delay, failure to thrive, microcephaly and defects in the respiratory chain (Gai et al. 2013; Huemer et al. 2015; Al-Shamsi et al. 2016). The c.1067delG variant is not observed in large population cohorts (Lek et al., 2016). The c.1067delG variant causes a frameshift starting with codon Glycine 356, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 15 of the new reading frame, denoted p.Gly356AlafsX15. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554219474; hg19: chr6-99353337;