chr1-224114351-C-A

Variant names:

• chr1-224114351-C-A
• rs1045848566
• NM_015176.4:c.222C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015176.4(FBXO28):​c.222C>A​(p.Asn74Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,447,532 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FBXO28 NM_015176.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15006375).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO28	NM_015176.4	MANE Select	c.222C>A	p.Asn74Lys	missense	Exon 1 of 5	NP_055991.1	Q9NVF7-1
	FBXO28	NM_001136115.3		c.222C>A	p.Asn74Lys	missense	Exon 1 of 4	NP_001129587.1	Q9NVF7-2
	FBXO28	NR_049764.2		n.241C>A		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO28	ENST00000366862.10	TSL:1 MANE Select	c.222C>A	p.Asn74Lys	missense	Exon 1 of 5	ENSP00000355827.5	Q9NVF7-1
	FBXO28	ENST00000424254.6	TSL:1	c.222C>A	p.Asn74Lys	missense	Exon 1 of 4	ENSP00000416888.2	Q9NVF7-2
	FBXO28	ENST00000483773.1	TSL:2	n.181C>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447532 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 718746

African (AFR) AF: 0.00 AC: 0 AN: 33080

American (AMR) AF: 0.0000232 AC: 1 AN: 43096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25688

East Asian (EAS) AF: 0.00 AC: 0 AN: 39122

South Asian (SAS) AF: 0.00 AC: 0 AN: 84080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5194

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105232

Other (OTH) AF: 0.00 AC: 0 AN: 59750

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.060
Sift	Benign	1.0	T
Sift4G	Benign	0.80	T
Polyphen		0.19	B
Vest4		0.44
MutPred		0.31		Gain of methylation at N74 (P = 0.011)
MVP		0.31
MPC		1.0
ClinPred		0.93	D
GERP RS		4.2
PromoterAI		-0.038	Neutral
Varity_R		0.10
gMVP		0.23
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs1045848566; hg19: chr1-224302053;