rs121918305

chr22-32475067-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• 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	UniProt
FBXO7	NM_012179.4	c.65C>T	p.Thr22Met	missense_variant	1/9	ENST00000266087.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXO7	ENST00000266087.12	c.65C>T	p.Thr22Met	missense_variant	1/9	1	NM_012179.4	P2
FBXO7	ENST00000492535.1	n.53C>T		non_coding_transcript_exon_variant	1/7	5
FBXO7	ENST00000425028.5	c.65C>T	p.Thr22Met	missense_variant, NMD_transcript_variant	1/9	5
FBXO7	ENST00000420700.5	c.65C>T	p.Thr22Met	missense_variant, NMD_transcript_variant	1/8	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, criteria provided, single submitter	clinical testing	Invitae	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 20, 2009	- -

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
MutationTaster	Benign	0.99	A
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;