rs1553292987

Variant names:

• chr1-224157682-G-T
• rs1553292987
• NM_015176.4:c.1043G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PM2 PM5 PP5_Very_Strong BP4

The NM_015176.4(FBXO28):​c.1043G>T​(p.Arg348Leu) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). 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)
• Consequence: FBXO28 NM_015176.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.78
• Publications: 1 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: Pathogenic. The variant received 11 ACMG points.

• 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 VariationId is 1343398.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 1-224157682-G-T is Pathogenic according to our data. Variant chr1-224157682-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2497912). . Strength limited to SUPPORTING due to the PP5.

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.1043G>T	p.Arg348Leu	missense	Exon 5 of 5	NP_055991.1	Q9NVF7-1
	FBXO28	NM_001136115.3		c.*307G>T		3_prime_UTR	Exon 4 of 4	NP_001129587.1	Q9NVF7-2
	FBXO28	NR_049764.2		n.923G>T		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO28	ENST00000366862.10	TSL:1 MANE Select	c.1043G>T	p.Arg348Leu	missense	Exon 5 of 5	ENSP00000355827.5	Q9NVF7-1
	FBXO28	ENST00000424254.6	TSL:1	c.*307G>T		3_prime_UTR	Exon 4 of 4	ENSP00000416888.2	Q9NVF7-2
	FBXO28	ENST00000523990.1	TSL:2	n.*523G>T		non_coding_transcript_exon	Exon 4 of 4	ENSP00000430632.1	B4E0H5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy 100 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.048
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		6.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.17
Sift	Uncertain	0.016	D
Sift4G	Benign	0.10	T
Polyphen		0.18	B
Vest4		0.61
MutPred		0.32		Loss of ubiquitination at K349 (P = 0.0435)
MVP		0.27
MPC		1.7
ClinPred		0.83	D
GERP RS		5.1
Varity_R		0.15
gMVP		0.19
Mutation Taster		=82/18	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: rs1553292987; hg19: chr1-224345384;