rs185850413

chr6-98874269-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001278716.2(FBXL4):c.*9A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,568,334 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).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (0 hom.)
• Consequence: FBXL4 NM_001278716.2 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.325

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-98874269-T-C is Benign according to our data. Variant chr6-98874269-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437827.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr6-98874269-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00118 (179/152214) while in subpopulation NFE AF= 0.00225 (153/67994). AF 95% confidence interval is 0.00196. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXL4	NM_001278716.2	c.*9A>G		3_prime_UTR_variant	10/10	ENST00000369244.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXL4	ENST00000369244.7	c.*9A>G		3_prime_UTR_variant	10/10	1	NM_001278716.2	P1
FBXL4	ENST00000229971.2	c.*9A>G		3_prime_UTR_variant	9/9	1		P1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00103 AC: 225 AN: 217768 Hom.: 0 AF XY: 0.00103 AC XY: 123 AN XY: 118948

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.000480

Gnomad ASJ exome AF: 0.000485

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000192

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.00144 AC: 2039 AN: 1416120 Hom.: 0 Cov.: 29 AF XY: 0.00137 AC XY: 965 AN XY: 703084

Gnomad4 AFR exome AF: 0.000390

Gnomad4 AMR exome AF: 0.000494

Gnomad4 ASJ exome AF: 0.000329

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000189

Gnomad4 NFE exome AF: 0.00175

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00118 AC: 179 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74438

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00225

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.00109

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial DNA depletion syndrome 13 Uncertain:1

Uncertain significance, criteria provided, single submitter

reference population

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

Aug 10, 2017

The NM_012160.4:c.*9A>G (NP_036292.2:p.=) [GRCH38: NC_000006.12:g.98874269T>C] variant in FBXL4 gene is interpretated to be a Uncertain Significance - Conflicting 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. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 13. BP4:Computational evidence/predictors indicate no impact on the FBXL4 structure, function, or protein-protein interaction. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Uncertain Significance - Conflicting Evidence. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 23, 2023

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.48
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs185850413; hg19: chr6-99322145;