Genetic Variant FBXO28:p.Leu48Phe (chr1-224114271-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015176.4(FBXO28):c.142C>T(p.Leu48Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000643 in 1,556,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

FBXO28
NM_015176.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.960

Publications

0 publications found

Variant links:

Genes affected

FBXO28 (HGNC:29046): (F-box protein 28) Members of the F-box protein family, such as FBXO28, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

FBXO28 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy 100
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

FBXO28 links:

ENSG00000293922 (HGNC:):

ENSG00000293922 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.071408).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015176.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXO28	NM_015176.4	MANE Select	c.142C>T	p.Leu48Phe	missense	Exon 1 of 5	NP_055991.1	Q9NVF7-1
FBXO28	NM_001136115.3		c.142C>T	p.Leu48Phe	missense	Exon 1 of 4	NP_001129587.1	Q9NVF7-2
FBXO28	NR_049764.2		n.161C>T		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXO28	ENST00000366862.10	TSL:1 MANE Select	c.142C>T	p.Leu48Phe	missense	Exon 1 of 5	ENSP00000355827.5	Q9NVF7-1
FBXO28	ENST00000424254.6	TSL:1	c.142C>T	p.Leu48Phe	missense	Exon 1 of 4	ENSP00000416888.2	Q9NVF7-2
FBXO28	ENST00000483773.1	TSL:2	n.101C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

161072

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000427

AC:

AN:

1404114

Hom.:

Cov.:

AF XY:

0.00000433

AC XY:

AN XY:

693268

show subpopulations

African (AFR)

AF:

0.000156

AC:

AN:

31986

American (AMR)

AF:

0.00

AC:

AN:

36488

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25198

East Asian (EAS)

AF:

0.0000274

AC:

AN:

36528

South Asian (SAS)

AF:

0.00

AC:

AN:

79748

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4680

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082154

Other (OTH)

AF:

0.00

AC:

AN:

58078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000263

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000192

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000712

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.00000868

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.013

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.69

M_CAP

Benign

0.024

MetaRNN

Benign

0.071

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

0.96

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.27

REVEL

Benign

0.074

Sift

Benign

0.18

Sift4G

Benign

0.16

Polyphen

0.070

Vest4

0.086

MutPred

0.10

Gain of glycosylation at P43 (P = 0.2413)

MVP

0.043

MPC

0.78

ClinPred

0.16

GERP RS

3.9

PromoterAI

0.025

Neutral

(source)

Varity_R

0.070

gMVP

0.053

Mutation Taster

=96/4

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.

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