6-98874285-G-C

Variant names:

• chr6-98874285-G-C
• rs767709670
• NM_001278716.2:c.1859C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001278716.2(FBXL4):​c.1859C>G​(p.Thr620Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000417 in 1,440,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: FBXL4 NM_001278716.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.57
• 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 3 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL4	NM_001278716.2	c.1859C>G	p.Thr620Ser	missense_variant	Exon 10 of 10	ENST00000369244.7	NP_001265645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL4	ENST00000369244.7	c.1859C>G	p.Thr620Ser	missense_variant	Exon 10 of 10	1	NM_001278716.2	ENSP00000358247.1
FBXL4	ENST00000229971.2	c.1859C>G	p.Thr620Ser	missense_variant	Exon 9 of 9	1		ENSP00000229971.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000861 AC: 2 AN: 232282 AF XY: 0.00000792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000417 AC: 6 AN: 1440206 Hom.: 0 Cov.: 30 AF XY: 0.00000698 AC XY: 5 AN XY: 716244

African (AFR) AF: 0.00 AC: 0 AN: 31824

American (AMR) AF: 0.00 AC: 0 AN: 37468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25308

East Asian (EAS) AF: 0.00 AC: 0 AN: 39260

South Asian (SAS) AF: 0.0000732 AC: 6 AN: 81976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105930

Other (OTH) AF: 0.00 AC: 0 AN: 59514

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial DNA depletion syndrome 13 Uncertain:1

Aug 10, 2017

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

The NM_012160.4:c.1859C>G (NP_036292.2:p.Thr620Ser) [GRCH38: NC_000006.12:g.98874285G>C] variant in FBXL4 gene is interpretated to be a Uncertain Significance - Insufficient Evidence based on ACMG guidelines (PMID: 25741868). This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Uncertain Significance - Insufficient Evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L
PhyloP100		9.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.46	N;N
REVEL	Benign	0.23
Sift	Benign	0.060	T;T
Sift4G	Benign	0.15	T;T
Polyphen		1.0	D;D
Vest4		0.56
MutPred		0.29		Gain of disorder (P = 0.0489);Gain of disorder (P = 0.0489);
MVP		0.69
MPC		0.38
ClinPred		0.65	D
GERP RS		6.0
Varity_R		0.16
gMVP		0.40
Mutation Taster		=79/21	polymorphism

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: rs767709670; hg19: chr6-99322161;