rs61744041

chr6-98905551-T-C

Variant summary

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

The NM_001278716.2(FBXL4):c.978A>G(p.Gln326=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,614,032 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (42 hom.)
• Consequence: FBXL4 NM_001278716.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.316

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=-0.81).
• BP6: Variant 6-98905551-T-C is Benign according to our data. Variant chr6-98905551-T-C is described in ClinVar as [Benign]. Clinvar id is 380510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-98905551-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.316 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00529 (806/152266) while in subpopulation SAS AF= 0.0124 (60/4826). AF 95% confidence interval is 0.00991. There are 6 homozygotes in gnomad4. There are 383 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXL4	NM_001278716.2	c.978A>G	p.Gln326=	synonymous_variant	6/10	ENST00000369244.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXL4	ENST00000369244.7	c.978A>G	p.Gln326=	synonymous_variant	6/10	1	NM_001278716.2	P1
FBXL4	ENST00000229971.2	c.978A>G	p.Gln326=	synonymous_variant	5/9	1		P1

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 799 AN: 152146 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00537

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00556 AC: 1398 AN: 251366 Hom.: 16 AF XY: 0.00608 AC XY: 826 AN XY: 135838

Gnomad AFR exome AF: 0.00695

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00724

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0148

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00535

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00543 AC: 7932 AN: 1461766 Hom.: 42 Cov.: 33 AF XY: 0.00574 AC XY: 4174 AN XY: 727184

Gnomad4 AFR exome AF: 0.00657

Gnomad4 AMR exome AF: 0.00327

Gnomad4 ASJ exome AF: 0.00697

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0149

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.00505

Gnomad4 OTH exome AF: 0.00520

GnomAD4 genome AF: 0.00529 AC: 806 AN: 152266 Hom.: 6 Cov.: 32 AF XY: 0.00514 AC XY: 383 AN XY: 74464

Gnomad4 AFR AF: 0.00611

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00537

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00597 Hom.: 2

Bravo AF: 0.00536

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00644

EpiControl AF: 0.00717

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	FBXL4: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 22, 2016

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. -

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.978A>G (NP_036292.2:p.Gln326=) [GRCH38: NC_000006.12:g.98905551T>C] 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. 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	-0.81
Cadd	Benign	0.49
Dann	Benign	0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61744041; hg19: chr6-99353427;