NM_001278716.2:c.1252G>C

Variant names:

• chr6-98899333-C-G
• rs542852839
• NM_001278716.2:c.1252G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_001278716.2(FBXL4):​c.1252G>C​(p.Ala418Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A418T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: FBXL4 NM_001278716.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 4.59
• 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 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_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001278716.2
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8
• PP5: Variant 6-98899333-C-G is Pathogenic according to our data. Variant chr6-98899333-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 976769.

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.1252G>C	p.Ala418Pro	missense	Exon 7 of 10	NP_001265645.1
	FBXL4	NM_012160.5		c.1252G>C	p.Ala418Pro	missense	Exon 6 of 9	NP_036292.2
	FBXL4	NR_103836.2		n.1237G>C		non_coding_transcript_exon	Exon 5 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL4	ENST00000369244.7	TSL:1 MANE Select	c.1252G>C	p.Ala418Pro	missense	Exon 7 of 10	ENSP00000358247.1
	FBXL4	ENST00000229971.2	TSL:1	c.1252G>C	p.Ala418Pro	missense	Exon 6 of 9	ENSP00000229971.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461732 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727170

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111926

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.22
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.024	D
Polyphen		0.93	P
Vest4		0.90
MutPred		0.63		Gain of disorder (P = 0.0502)
MVP		0.61
MPC		0.36
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.76
gMVP		0.87
Mutation Taster		=51/49	disease causing (ClinVar)

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: rs542852839; hg19: chr6-99347209;