rs114916821

Positions:

• chr6-98926521-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000369244.7(FBXL4):​c.468T>C​(p.Ala156=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000598 in 1,613,486 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (6 hom.)
• Consequence: FBXL4 ENST00000369244.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.131

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 6-98926521-A-G is Benign according to our data. Variant chr6-98926521-A-G is described in ClinVar as [Benign]. Clinvar id is 380454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-98926521-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.131 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000959 (146/152304) while in subpopulation EAS AF= 0.0191 (99/5176). AF 95% confidence interval is 0.0161. There are 2 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXL4	NM_001278716.2	c.468T>C	p.Ala156=	synonymous_variant	4/10	ENST00000369244.7	NP_001265645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXL4	ENST00000369244.7	c.468T>C	p.Ala156=	synonymous_variant	4/10	1	NM_001278716.2	ENSP00000358247	P1
FBXL4	ENST00000229971.2	c.468T>C	p.Ala156=	synonymous_variant	3/9	1		ENSP00000229971	P1

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 146 AN: 152186 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0191

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00171 AC: 428 AN: 250648 Hom.: 5 AF XY: 0.00162 AC XY: 219 AN XY: 135428

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.0173

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000561 AC: 819 AN: 1461182 Hom.: 6 Cov.: 31 AF XY: 0.000594 AC XY: 432 AN XY: 726780

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00968

Gnomad4 SAS exome AF: 0.00131

Gnomad4 FIN exome AF: 0.00187

Gnomad4 NFE exome AF: 0.0000945

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.000959 AC: 146 AN: 152304 Hom.: 2 Cov.: 33 AF XY: 0.00133 AC XY: 99 AN XY: 74480

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.0191

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.000907

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2019	- -

Mitochondrial DNA depletion syndrome 13 Benign:1

Benign, 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.468T>C (NP_036292.2:p.Ala156=) [GRCH38: NC_000006.12:g.98926521A>G] variant in FBXL4 gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant meets one or more of the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 13. BS2:Observation of the variant is in controls is inconsistent with penetrance of 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 Benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.8
DANN	Benign	0.65

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: rs114916821; hg19: chr6-99374397;