rs17058965

Variant names:

• chr6-98926560-T-C
• rs17058965
• NM_001278716.2:c.429A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001278716.2(FBXL4):​c.429A>G​(p.Leu143Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000833 in 1,614,162 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (5 hom.)
• Consequence: FBXL4 NM_001278716.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.37
• Publications: 2 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 DNA depletion syndrome 13

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 6-98926560-T-C is Benign according to our data. Variant chr6-98926560-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00438 (667/152302) while in subpopulation AFR AF = 0.0154 (640/41556). AF 95% confidence interval is 0.0144. There are 5 homozygotes in GnomAd4. There are 307 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL4	NM_001278716.2	MANE Select	c.429A>G	p.Leu143Leu	synonymous	Exon 4 of 10	NP_001265645.1
	FBXL4	NM_012160.5		c.429A>G	p.Leu143Leu	synonymous	Exon 3 of 9	NP_036292.2
	FBXL4	NR_103836.2		n.760A>G		non_coding_transcript_exon	Exon 3 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL4	ENST00000369244.7	TSL:1 MANE Select	c.429A>G	p.Leu143Leu	synonymous	Exon 4 of 10	ENSP00000358247.1
	FBXL4	ENST00000229971.2	TSL:1	c.429A>G	p.Leu143Leu	synonymous	Exon 3 of 9	ENSP00000229971.1

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 666 AN: 152184 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00119 AC: 298 AN: 251358 AF XY: 0.000861

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000463 AC: 677 AN: 1461860 Hom.: 5 Cov.: 31 AF XY: 0.000402 AC XY: 292 AN XY: 727224

African (AFR) AF: 0.0170 AC: 570 AN: 33478

American (AMR) AF: 0.000783 AC: 35 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111984

Other (OTH) AF: 0.000927 AC: 56 AN: 60396

GnomAD4 genome AF: 0.00438 AC: 667 AN: 152302 Hom.: 5 Cov.: 32 AF XY: 0.00412 AC XY: 307 AN XY: 74484

African (AFR) AF: 0.0154 AC: 640 AN: 41556

American (AMR) AF: 0.00118 AC: 18 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00207 Hom.: 0

Bravo AF: 0.00508

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Mitochondrial DNA depletion syndrome 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.74
PhyloP100		1.4
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17058965; hg19: chr6-99374436; COSMIC: COSV57747252;