rs372735676

Variant names:

• chr6-98926944-A-C
• rs372735676
• NM_001278716.2:c.45T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-98926944-A-C
• chr6-98926944-A-G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001278716.2(FBXL4):​c.45T>G​(p.Tyr15*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,856 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y15Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FBXL4 NM_001278716.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.24
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 84 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-98926944-A-C is Pathogenic according to our data. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-98926944-A-C is described in CliVar as Pathogenic. Clinvar id is 1454261.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL4	NM_001278716.2	c.45T>G	p.Tyr15*	stop_gained	Exon 4 of 10	ENST00000369244.7	NP_001265645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL4	ENST00000369244.7	c.45T>G	p.Tyr15*	stop_gained	Exon 4 of 10	1	NM_001278716.2	ENSP00000358247.1
FBXL4	ENST00000229971.2	c.45T>G	p.Tyr15*	stop_gained	Exon 3 of 9	1		ENSP00000229971.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111990

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr15*) in the FBXL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBXL4 are known to be pathogenic (PMID: 23993193, 23993194, 25868664). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FBXL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1454261). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.2
Vest4		0.50
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=7/193	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs372735676; hg19: chr6-99374820;