Genetic Variant FBXO28:p.Arg348Gln (chr1-224157682-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_015176.4(FBXO28):c.1043G>A(p.Arg348Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R348G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FBXO28
NM_015176.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.78

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-224157681-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1343398.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.1902394).

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.1043G>A	p.Arg348Gln	missense	Exon 5 of 5	NP_055991.1	Q9NVF7-1
FBXO28	NM_001136115.3		c.*307G>A		3_prime_UTR	Exon 4 of 4	NP_001129587.1	Q9NVF7-2
FBXO28	NR_049764.2		n.923G>A		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXO28	ENST00000366862.10	TSL:1 MANE Select	c.1043G>A	p.Arg348Gln	missense	Exon 5 of 5	ENSP00000355827.5	Q9NVF7-1
FBXO28	ENST00000424254.6	TSL:1	c.*307G>A		3_prime_UTR	Exon 4 of 4	ENSP00000416888.2	Q9NVF7-2
FBXO28	ENST00000523990.1	TSL:2	n.*523G>A		non_coding_transcript_exon	Exon 4 of 4	ENSP00000430632.1	B4E0H5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1455812

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724308

African (AFR)

AF:

0.00

AC:

AN:

32784

American (AMR)

AF:

0.00

AC:

AN:

42746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25868

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

85188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110414

Other (OTH)

AF:

0.00

AC:

AN:

60062

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

Eigen

Benign

-0.11

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

M_CAP

Benign

0.0049

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

6.8

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.51

REVEL

Benign

0.13

Sift

Benign

0.037

Sift4G

Benign

0.098

Polyphen

0.0020

Vest4

0.53

MutPred

0.27

Gain of ubiquitination at K350 (P = 0.0371)

MVP

0.29

MPC

1.7

ClinPred

0.82

GERP RS

5.1

Varity_R

0.085

gMVP

0.15

Mutation Taster

=89/11

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over