rs1553292987

Positions:

• chr1-224157682-G-A
• chr1-224157682-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_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. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.78

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 4 ACMG points.

• PM1: In a region_of_interest Disordered (size 40) in uniprot entity FBX28_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_015176.4
• 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 id is 1343398.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1902394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO28	NM_015176.4	c.1043G>A	p.Arg348Gln	missense_variant	5/5	ENST00000366862.10	NP_055991.1
FBXO28	NM_001136115.3	c.*307G>A		3_prime_UTR_variant	4/4		NP_001129587.1
FBXO28	NR_049764.2	n.923G>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO28	ENST00000366862.10	c.1043G>A	p.Arg348Gln	missense_variant	5/5	1	NM_015176.4	ENSP00000355827.5
FBXO28	ENST00000424254.6	c.*307G>A		3_prime_UTR_variant	4/4	1		ENSP00000416888.2
FBXO28	ENST00000523990.1	n.*523G>A		non_coding_transcript_exon_variant	4/4	2		ENSP00000430632.1
FBXO28	ENST00000523990.1	n.*523G>A		3_prime_UTR_variant	4/4	2		ENSP00000430632.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1455812 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 724308

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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.13
Sift	Benign	0.037	D
Sift4G	Benign	0.098	T
Polyphen		0.0020	B
Vest4		0.53
MutPred		0.27		Gain of ubiquitination at K350 (P = 0.0371);
MVP		0.29
MPC		1.7
ClinPred		0.82	D
GERP RS		5.1
Varity_R		0.085
gMVP		0.15

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: rs1553292987; hg19: chr1-224345384;