22-32475003-A-C

Variant names:

• chr22-32475003-A-C
• rs753392528
• NM_012179.4:c.1A>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_012179.4(FBXO7):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,383,780 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: 0.000013 (0 hom.)
• Consequence: FBXO7 NM_012179.4 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.91
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• parkinsonian-pyramidal syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 11 pathogenic variants. Next in-frame start position is after 115 codons. Genomic position: 32479201. Lost 0.219 part of the original CDS.
• PP5: Variant 22-32475003-A-C is Pathogenic according to our data. Variant chr22-32475003-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2887235.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012179.4. 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
	FBXO7	NM_012179.4	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	NP_036311.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO7	ENST00000266087.12	TSL:1 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	ENSP00000266087.7	Q9Y3I1-1
	FBXO7	ENST00000886524.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 10	ENSP00000556583.1
	FBXO7	ENST00000920428.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	ENSP00000590487.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000762 AC: 1 AN: 131310 AF XY: 0.0000139

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 18 AN: 1383780 Hom.: 0 Cov.: 31 AF XY: 0.0000176 AC XY: 12 AN XY: 682758

African (AFR) AF: 0.00 AC: 0 AN: 30442

American (AMR) AF: 0.00 AC: 0 AN: 35452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24968

East Asian (EAS) AF: 0.00 AC: 0 AN: 35128

South Asian (SAS) AF: 0.000216 AC: 17 AN: 78632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4084

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076332

Other (OTH) AF: 0.00 AC: 0 AN: 57500

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000319 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Parkinsonian-pyramidal syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.55	T
PhyloP100		1.9
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.61
MutPred		0.74		Loss of catalytic residue at M1 (P = 0.0047)
MVP		0.40
ClinPred		0.74	D
GERP RS		4.4
PromoterAI		-0.29	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.97
gMVP		0.66
Mutation Taster		=5/195	disease causing

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: rs753392528; hg19: chr22-32870990;