chr1-224114325-G-C

Position:

• chr1-224114325-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015176.4(FBXO28):​c.196G>C​(p.Ala66Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBXO28 NM_015176.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.40

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32470608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO28	NM_015176.4	c.196G>C	p.Ala66Pro	missense_variant	1/5	ENST00000366862.10	NP_055991.1
FBXO28	NM_001136115.3	c.196G>C	p.Ala66Pro	missense_variant	1/4		NP_001129587.1
FBXO28	NR_049764.2	n.215G>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO28	ENST00000366862.10	c.196G>C	p.Ala66Pro	missense_variant	1/5	1	NM_015176.4	ENSP00000355827.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy 100 Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Nov 26, 2024

The heterozygous p.Ala66Pro variant in FBXO28 was identified by our study in 1 individual with developmental and epileptic encephalopathy (PubMed: 33280099). Trio exome analysis showed this variant to be de novo. The p.Ala66Pro variant in FBXO28 has not been previously reported in the literature in individuals with developmental and epileptic encephalopathy, and was absent from large population studies. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala66Pro variant is uncertain. ACMG/AMP Criteria applied: BP4, PM2_supporting, PS2_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.23
Sift	Benign	0.12	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.96	P;.
Vest4		0.51
MutPred		0.50		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.15
MPC		1.8
ClinPred		0.86	D
GERP RS		5.0
Varity_R		0.30
gMVP		0.58

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.

Other links and lift over

hg19: chr1-224302027;