1-224114351-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

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=0.15006375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO28	NM_015176.4	c.222C>A	p.Asn74Lys	missense_variant	Exon 1 of 5	ENST00000366862.10	NP_055991.1
FBXO28	NM_001136115.3	c.222C>A	p.Asn74Lys	missense_variant	Exon 1 of 4		NP_001129587.1
FBXO28	NR_049764.2	n.241C>A		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO28	ENST00000366862.10	c.222C>A	p.Asn74Lys	missense_variant	Exon 1 of 5	1	NM_015176.4	ENSP00000355827.5

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000232

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.: 33

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.222C>A (p.N74K) alteration is located in exon 1 (coding exon 1) of the FBXO28 gene. This alteration results from a C to A substitution at nucleotide position 222, causing the asparagine (N) at amino acid position 74 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.32	N;N
REVEL	Benign	0.060
Sift	Benign	1.0	T;T
Sift4G	Benign	0.80	T;T
Polyphen		0.19	B;.
Vest4		0.44
MutPred		0.31		Gain of methylation at N74 (P = 0.011);Gain of methylation at N74 (P = 0.011);
MVP		0.31
MPC		1.0
ClinPred		0.93	D
GERP RS		4.2
Varity_R		0.10
gMVP		0.23

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

LitVar

Other links and lift over

dbSNP: rs1045848566; hg19: chr1-224302053;