6-98874325-T-C

Variant names:

• chr6-98874325-T-C
• NM_001278716.2:c.1819A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001278716.2(FBXL4):​c.1819A>G​(p.Asn607Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBXL4 NM_001278716.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87
• 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.

• PM1: In a repeat LRR 9 (size 25) in uniprot entity FBXL4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24484718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL4	NM_001278716.2	c.1819A>G	p.Asn607Asp	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.1819A>G	p.Asn607Asp	missense_variant	Exon 10 of 10	1	NM_001278716.2	ENSP00000358247.1
FBXL4	ENST00000229971.2	c.1819A>G	p.Asn607Asp	missense_variant	Exon 9 of 9	1		ENSP00000229971.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455140 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723796

African (AFR) AF: 0.00 AC: 0 AN: 32978

American (AMR) AF: 0.00 AC: 0 AN: 42606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39484

South Asian (SAS) AF: 0.00 AC: 0 AN: 84868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110072

Other (OTH) AF: 0.00 AC: 0 AN: 60124

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1819A>G (p.N607D) alteration is located in exon 9 (coding exon 7) of the FBXL4 gene. This alteration results from a A to G substitution at nucleotide position 1819, causing the asparagine (N) at amino acid position 607 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T;T
Eigen	Benign	0.024
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	.;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
PhyloP100		4.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.060
Sift	Benign	0.041	D;D
Sift4G	Benign	0.27	T;T
Polyphen		0.030	B;B
Vest4		0.36
MutPred		0.60		Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.43
MPC		0.079
ClinPred		0.59	D
GERP RS		6.0
Varity_R		0.12
gMVP		0.33
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr6-99322201;