6-98874356-C-T

Variant names:

• chr6-98874356-C-T
• rs745713189
• NM_001278716.2:c.1788G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_001278716.2(FBXL4):​c.1788G>A​(p.Ser596Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S596S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: FBXL4 NM_001278716.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.50
• 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 disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome 13

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 6-98874356-C-T is Benign according to our data. Variant chr6-98874356-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437818.
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL4	NM_001278716.2	MANE Select	c.1788G>A	p.Ser596Ser	synonymous	Exon 10 of 10	NP_001265645.1	Q9UKA2
	FBXL4	NM_012160.5		c.1788G>A	p.Ser596Ser	synonymous	Exon 9 of 9	NP_036292.2
	FBXL4	NR_103836.2		n.1773G>A		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL4	ENST00000369244.7	TSL:1 MANE Select	c.1788G>A	p.Ser596Ser	synonymous	Exon 10 of 10	ENSP00000358247.1	Q9UKA2
	FBXL4	ENST00000229971.2	TSL:1	c.1788G>A	p.Ser596Ser	synonymous	Exon 9 of 9	ENSP00000229971.1	Q9UKA2
	FBXL4	ENST00000892543.1		c.1809G>A	p.Ser603Ser	synonymous	Exon 10 of 10	ENSP00000562602.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250200 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460678 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726682

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39600

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111442

Other (OTH) AF: 0.0000166 AC: 1 AN: 60334

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000193 Hom.: 0

ClinVar

ClinVar submissions

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.0
DANN	Benign	0.67
PhyloP100		-1.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs745713189; hg19: chr6-99322232; COSMIC: COSV57748382;