Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001278716.2(FBXL4):c.978A>G(p.Gln326Gln) 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

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.316

Publications

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

FBXL4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 380510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FBXL4	NM_001278716.2	MANE Select	c.978A>G	p.Gln326Gln	synonymous	Exon 6 of 10	NP_001265645.1
FBXL4	NM_012160.5		c.978A>G	p.Gln326Gln	synonymous	Exon 5 of 9	NP_036292.2
FBXL4	NR_103836.2		n.963A>G		non_coding_transcript_exon	Exon 4 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL4	ENST00000369244.7	TSL:1 MANE Select	c.978A>G	p.Gln326Gln	synonymous	Exon 6 of 10	ENSP00000358247.1
	FBXL4	ENST00000229971.2	TSL:1	c.978A>G	p.Gln326Gln	synonymous	Exon 5 of 9	ENSP00000229971.1

Frequencies

GnomAD3 genomes

AF:

0.00525

AC:

799

AN:

152146

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00556

AC:

1398

AN:

251366

AF XY:

0.00608

show subpopulations

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 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.:

Cov.:

AF XY:

0.00574

AC XY:

4174

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.00657

AC:

220

AN:

33472

American (AMR)

AF:

0.00327

AC:

146

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00697

AC:

182

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0149

AC:

1286

AN:

86256

European-Finnish (FIN)

AF:

0.00129

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0166

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00505

AC:

5619

AN:

1111938

Other (OTH)

AF:

0.00520

AC:

314

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

459

918

1376

1835

2294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

218

436

654

872

1090

<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:

0.00529

AC:

806

AN:

152266

Hom.:

Cov.:

AF XY:

0.00514

AC XY:

383

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00611

AC:

254

AN:

41558

American (AMR)

AF:

0.00464

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.0124

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00537

AC:

365

AN:

68008

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

131

174

218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00597

Hom.:

Bravo

AF:

0.00536

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00644

EpiControl

AF:

0.00717

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Mitochondrial DNA depletion syndrome 13 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.49

(source)

DANN

Benign

0.28

PhyloP100

-0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(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.

rs61744041

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over