rs182139048

Positions:

• chr6-98899254-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001278716.2(FBXL4):​c.1317+14A>G variant causes a intron change. The variant allele was found at a frequency of 0.00111 in 1,610,084 control chromosomes in the GnomAD database, including 3 homozygotes. 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 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: FBXL4 NM_001278716.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.79

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-98899254-T-C is Benign according to our data. Variant chr6-98899254-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 384777.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}. Variant chr6-98899254-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00114 (1667/1457750) while in subpopulation NFE AF= 0.00114 (1263/1109148). AF 95% confidence interval is 0.00109. There are 3 homozygotes in gnomad4_exome. There are 752 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXL4	NM_001278716.2	c.1317+14A>G		intron_variant		ENST00000369244.7	NP_001265645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXL4	ENST00000369244.7	c.1317+14A>G		intron_variant		1	NM_001278716.2	ENSP00000358247.1
FBXL4	ENST00000229971.2	c.1317+14A>G		intron_variant		1		ENSP00000229971.1

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000961 AC: 240 AN: 249642 Hom.: 0 AF XY: 0.000934 AC XY: 126 AN XY: 134918

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000329

Gnomad FIN exome AF: 0.00431

Gnomad NFE exome AF: 0.000974

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00114 AC: 1667 AN: 1457750 Hom.: 3 Cov.: 33 AF XY: 0.00104 AC XY: 752 AN XY: 724540

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000383

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000314

Gnomad4 FIN exome AF: 0.00530

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.00120

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74478

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000491

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

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.1317+14A>G (NP_036292.2:p.=) [GRCH38: NC_000006.12:g.98899254T>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. BP4:Computational evidence/predictors indicate no impact on the FBXL4 structure, function, or protein-protein interaction. BP5:The variant is found in a case with alternate cuase. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Uncertain Significance - Conflicting Evidence. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 15, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	14
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs182139048; hg19: chr6-99347130;