15-75917301-T-C

Position:

• chr15-75917301-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_147188.3(FBXO22):​c.535T>C​(p.Phe179Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,459,278 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: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: FBXO22 NM_147188.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.24

Genes affected

FBXO22 (HGNC:13593): (F-box protein 22) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class and, as a transcriptional target of the tumor protein p53, is thought to be involved in degradation of specific proteins in response to p53 induction. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]

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=0.21544704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO22	NM_147188.3	c.535T>C	p.Phe179Leu	missense_variant	5/7	ENST00000308275.8	NP_671717.1
FBXO22	NM_012170.4	c.535T>C	p.Phe179Leu	missense_variant	5/6		NP_036302.1
FBXO22	XM_047432382.1	c.223T>C	p.Phe75Leu	missense_variant	4/6		XP_047288338.1
FBXO22	NR_037623.2	n.482T>C		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO22	ENST00000308275.8	c.535T>C	p.Phe179Leu	missense_variant	5/7	1	NM_147188.3	ENSP00000307833.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459278 Hom.: 0 Cov.: 29 AF XY: 0.00000689 AC XY: 5 AN XY: 726116

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2022

The c.535T>C (p.F179L) alteration is located in exon 5 (coding exon 5) of the FBXO22 gene. This alteration results from a T to C substitution at nucleotide position 535, causing the phenylalanine (F) at amino acid position 179 to be replaced by a leucine (L). 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	0.73
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Benign	0.86
DEOGEN2	Benign	0.011	T;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.16	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.60	T;T;D
Polyphen		0.048	B;D;.
Vest4		0.73
MutPred		0.33		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);.;
MVP		0.24
MPC		0.53
ClinPred		0.72	D
GERP RS		5.6
Varity_R		0.12
gMVP		0.69

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: rs1900212749; hg19: chr15-76209642;