rs121918305

Positions:

• chr22-32475067-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_012179.4(FBXO7):​c.65C>T​(p.Thr22Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000502 in 1,393,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: FBXO7 NM_012179.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.94

Genes affected

FBXO7 (HGNC:13586): (F-box protein 7) 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 it may play a role in regulation of hematopoiesis. Alternatively spliced transcript variants of this gene have been identified with the full-length natures of only some variants being determined. [provided by RefSeq, Jul 2008]

FBXO7 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a mutagenesis_site Impairs interaction with PRKN. (size 0) in uniprot entity FBX7_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 22-32475067-C-T is Pathogenic according to our data. Variant chr22-32475067-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4811.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-32475067-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO7	NM_012179.4	c.65C>T	p.Thr22Met	missense_variant	1/9	ENST00000266087.12	NP_036311.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO7	ENST00000266087.12	c.65C>T	p.Thr22Met	missense_variant	1/9	1	NM_012179.4	ENSP00000266087.7
FBXO7	ENST00000420700.5	n.65C>T		non_coding_transcript_exon_variant	1/8	5		ENSP00000406155.1
FBXO7	ENST00000425028.5	n.65C>T		non_coding_transcript_exon_variant	1/9	5		ENSP00000395823.1
FBXO7	ENST00000492535.1	n.53C>T		non_coding_transcript_exon_variant	1/7	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000502 AC: 7 AN: 1393750 Hom.: 0 Cov.: 31 AF XY: 0.00000291 AC XY: 2 AN XY: 687568

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: 0.00000557

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000896 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Parkinsonian-pyramidal syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 20, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 22 of the FBXO7 protein (p.Thr22Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive early-onset parkinsonian-pyramidal syndrome (PMID: 19038853). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4811). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects FBXO7 function (PMID: 21347293, 23933751, 26310625, 27503909). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.73		Loss of glycosylation at T22 (P = 0.034);
MVP		0.73
MPC		0.40
ClinPred		0.98	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.58

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: rs121918305; hg19: chr22-32871054;