Genetic Variant FBXO28:p.Pro33Ser (chr1-224114226-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015176.4(FBXO28):c.97C>T(p.Pro33Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

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

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.60

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 links:

LOC105373056 (HGNC:):

LOC105373056 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.102779806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO28	NM_015176.4 link	c.97C>T	p.Pro33Ser	missense_variant	Exon 1 of 5	ENST00000366862.10	NP_055991.1	Q9NVF7-1
FBXO28	NM_001136115.3 link	c.97C>T	p.Pro33Ser	missense_variant	Exon 1 of 4		NP_001129587.1	Q9NVF7-2
FBXO28	NR_049764.2 link	n.116C>T		non_coding_transcript_exon_variant	Exon 1 of 4
LOC105373056	XR_007066897.1 link	n.-186G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO28	ENST00000366862.10 link	c.97C>T	p.Pro33Ser	missense_variant	Exon 1 of 5	1	NM_015176.4	ENSP00000355827.5		Q9NVF7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1398314

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689804

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

FBXO28-related developmental and epileptic encephalopathy

Uncertain:1

Jan 27, 2021

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FBXO28 c.97C>T (p.Pro33Ser) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. The p.Pro33Ser variant is located in the first of five exons encoded by the canonical transcript (NM_015176.3), upstream of the F-box domain. Based on the limited evidence, the p.Pro33Ser variant is classified as a variant of uncertain significance for FBXO28-related developmental and epileptic encephalopathy. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.014

T;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.70

T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.63

N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.18

N;N

REVEL

Benign

0.086

Sift

Benign

0.38

T;T

Sift4G

Benign

0.88

T;T

Polyphen

0.0

B;.

Vest4

0.25

MutPred

0.20

Loss of catalytic residue at P33 (P = 0.0011);Loss of catalytic residue at P33 (P = 0.0011);

MVP

0.093

MPC

0.72

ClinPred

0.16

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.054

gMVP

0.21

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over