Genetic Variant FBXL4:p.Gly523Gly (chr6-98875548-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001278716.2(FBXL4):c.1569G>A(p.Gly523Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,614,018 control chromosomes in the GnomAD database, including 3,800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G523G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.066 ( 355 hom., cov: 32)

Exomes 𝑓: 0.066 ( 3445 hom. )

Consequence

FBXL4
NM_001278716.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.927

Publications

8 publications found

Variant links:

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 disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial DNA depletion syndrome 13
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

FBXL4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 6-98875548-C-T is Benign according to our data. Variant chr6-98875548-C-T is described in ClinVar as Benign. ClinVar VariationId is 260208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.927 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0713 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXL4	NM_001278716.2	MANE Select	c.1569G>A	p.Gly523Gly	synonymous	Exon 9 of 10	NP_001265645.1	Q9UKA2
FBXL4	NM_012160.5		c.1569G>A	p.Gly523Gly	synonymous	Exon 8 of 9	NP_036292.2
FBXL4	NR_103836.2		n.1554G>A		non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXL4	ENST00000369244.7	TSL:1 MANE Select	c.1569G>A	p.Gly523Gly	synonymous	Exon 9 of 10	ENSP00000358247.1	Q9UKA2
FBXL4	ENST00000229971.2	TSL:1	c.1569G>A	p.Gly523Gly	synonymous	Exon 8 of 9	ENSP00000229971.1	Q9UKA2
FBXL4	ENST00000892543.1		c.1590G>A	p.Gly530Gly	synonymous	Exon 9 of 10	ENSP00000562602.1

Frequencies

GnomAD3 genomes

AF:

0.0658

AC:

10011

AN:

152078

Hom.:

354

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0701

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0459

Gnomad ASJ

AF:

0.0948

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0479

Gnomad FIN

AF:

0.0634

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0730

Gnomad OTH

AF:

0.0712

GnomAD2 exomes

AF:

0.0566

AC:

14210

AN:

251030

AF XY:

0.0568

show subpopulations

Gnomad AFR exome

AF:

0.0688

Gnomad AMR exome

AF:

0.0302

Gnomad ASJ exome

AF:

0.0975

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0610

Gnomad NFE exome

AF:

0.0694

Gnomad OTH exome

AF:

0.0660

GnomAD4 exome

AF:

0.0664

AC:

96995

AN:

1461822

Hom.:

3445

Cov.:

AF XY:

0.0654

AC XY:

47566

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.0698

AC:

2336

AN:

33476

American (AMR)

AF:

0.0321

AC:

1437

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0968

AC:

2529

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39696

South Asian (SAS)

AF:

0.0479

AC:

4130

AN:

86258

European-Finnish (FIN)

AF:

0.0636

AC:

3397

AN:

53416

Middle Eastern (MID)

AF:

0.0708

AC:

408

AN:

5766

European-Non Finnish (NFE)

AF:

0.0707

AC:

78626

AN:

1111974

Other (OTH)

AF:

0.0684

AC:

4128

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

5688

11376

17065

22753

28441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2924

5848

8772

11696

14620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0658

AC:

10017

AN:

152196

Hom.:

355

Cov.:

AF XY:

0.0655

AC XY:

4877

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0700

AC:

2909

AN:

41534

American (AMR)

AF:

0.0459

AC:

701

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0948

AC:

329

AN:

3470

East Asian (EAS)

AF:

0.000772

AC:

AN:

5184

South Asian (SAS)

AF:

0.0483

AC:

233

AN:

4820

European-Finnish (FIN)

AF:

0.0634

AC:

672

AN:

10598

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0730

AC:

4961

AN:

67992

Other (OTH)

AF:

0.0710

AC:

150

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

489

978

1468

1957

2446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0662

Hom.:

489

Bravo

AF:

0.0645

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.0690

EpiControl

AF:

0.0685

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Mitochondrial DNA depletion syndrome 13 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

1.4

(source)

DANN

Benign

0.57

PhyloP100

-0.93

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over