NM_001278716.2:c.*90G>C

Variant names:

• chr6-98874188-C-G
• rs111226417
• NM_001278716.2:c.*90G>C

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.*90G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 937,880 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (3 hom.)
• Consequence: FBXL4 NM_001278716.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0630
• 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=-0.78).
• BP6: Variant 6-98874188-C-G is Benign according to our data. Variant chr6-98874188-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1181505.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 = 0.00542 (825/152134) while in subpopulation AFR AF = 0.0188 (779/41518). AF 95% confidence interval is 0.0177. There are 10 homozygotes in GnomAd4. There are 375 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL4	NM_001278716.2	c.*90G>C		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.*90G>C		3_prime_UTR_variant	Exon 10 of 10	1	NM_001278716.2	ENSP00000358247.1
FBXL4	ENST00000229971.2	c.*90G>C		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000229971.1

Frequencies

GnomAD3 genomes AF: 0.00537 AC: 816 AN: 152018 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00336

GnomAD4 exome AF: 0.000507 AC: 398 AN: 785746 Hom.: 3 Cov.: 10 AF XY: 0.000459 AC XY: 181 AN XY: 394164

African (AFR) AF: 0.0182 AC: 312 AN: 17116

American (AMR) AF: 0.00133 AC: 23 AN: 17322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14960

East Asian (EAS) AF: 0.00 AC: 0 AN: 30254

South Asian (SAS) AF: 0.0000301 AC: 1 AN: 33270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44482

Middle Eastern (MID) AF: 0.000599 AC: 2 AN: 3338

European-Non Finnish (NFE) AF: 0.0000221 AC: 13 AN: 589476

Other (OTH) AF: 0.00132 AC: 47 AN: 35528

GnomAD4 genome AF: 0.00542 AC: 825 AN: 152134 Hom.: 10 Cov.: 32 AF XY: 0.00504 AC XY: 375 AN XY: 74366

African (AFR) AF: 0.0188 AC: 779 AN: 41518

American (AMR) AF: 0.00229 AC: 35 AN: 15276

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: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67970

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.000210 Hom.: 0

Bravo AF: 0.00635

Asia WGS AF: 0.00203 AC: 7 AN: 3466

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 09, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.1
DANN	Benign	0.66
PhyloP100		0.063
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs111226417; hg19: chr6-99322064;