rs142988015

Variant names:

• chr6-98874273-T-C
• rs142988015
• NM_001278716.2:c.*5A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001278716.2(FBXL4):​c.*5A>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 0.000648 in 1,575,596 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (4 hom.)
• Consequence: FBXL4 NM_001278716.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.641
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-98874273-T-C is Benign according to our data. Variant chr6-98874273-T-C is described in ClinVar as [Benign]. Clinvar id is 437826.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 = 0.00336 (511/152250) while in subpopulation AFR AF = 0.0111 (463/41560). AF 95% confidence interval is 0.0103. There are 3 homozygotes in GnomAd4. There are 234 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL4	NM_001278716.2	c.*5A>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000369244.7	NP_001265645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL4	ENST00000369244.7	c.*5A>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_001278716.2	ENSP00000358247.1
FBXL4	ENST00000229971.2	c.*5A>G		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000229971.1

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 509 AN: 152132 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

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: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000906 AC: 201 AN: 221752 AF XY: 0.000645

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.000788

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000660

Gnomad OTH exome AF: 0.000192

GnomAD4 exome AF: 0.000358 AC: 510 AN: 1423346 Hom.: 4 Cov.: 30 AF XY: 0.000314 AC XY: 222 AN XY: 707060

African (AFR) AF: 0.0121 AC: 376 AN: 31014

American (AMR) AF: 0.00146 AC: 49 AN: 33676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24568

East Asian (EAS) AF: 0.00 AC: 0 AN: 38768

South Asian (SAS) AF: 0.00 AC: 0 AN: 78466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52948

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5624

European-Non Finnish (NFE) AF: 0.0000246 AC: 27 AN: 1099560

Other (OTH) AF: 0.000971 AC: 57 AN: 58722

GnomAD4 genome AF: 0.00336 AC: 511 AN: 152250 Hom.: 3 Cov.: 32 AF XY: 0.00314 AC XY: 234 AN XY: 74464

African (AFR) AF: 0.0111 AC: 463 AN: 41560

American (AMR) AF: 0.00262 AC: 40 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00168 Hom.: 0

Bravo AF: 0.00446

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome 13 Benign:1

Aug 10, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: reference population

The NM_012160.4:c.*5A>G (NP_036292.2:p.=) [GRCH38: NC_000006.12:g.98874273T>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. 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. -

FBXL4-related disorder Benign:1

Mar 30, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Feb 04, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.28
DANN	Benign	0.70
PhyloP100		-0.64
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

Other links and lift over

dbSNP: rs142988015; hg19: chr6-99322149;