NM_012179.4:c.65C>T

Variant names:

• chr22-32475067-C-T
• rs121918305
• NM_012179.4:c.65C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: FBXO7 NM_012179.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.94
• Publications: 28 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 12 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/Likely_pathogenic. ClinVar VariationId is 4811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.65C>T	p.Thr22Met	missense	Exon 1 of 9	NP_036311.3
	FBXO7	NM_001033024.2		c.-295C>T		upstream_gene	N/A	NP_001028196.1	Q9Y3I1-2
	FBXO7	NM_001257990.2		c.-552C>T		upstream_gene	N/A	NP_001244919.1	Q9Y3I1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO7	ENST00000266087.12	TSL:1 MANE Select	c.65C>T	p.Thr22Met	missense	Exon 1 of 9	ENSP00000266087.7	Q9Y3I1-1
	FBXO7	ENST00000886524.1		c.65C>T	p.Thr22Met	missense	Exon 1 of 10	ENSP00000556583.1
	FBXO7	ENST00000920428.1		c.65C>T	p.Thr22Met	missense	Exon 1 of 9	ENSP00000590487.1

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

African (AFR) AF: 0.00 AC: 0 AN: 31136

American (AMR) AF: 0.00 AC: 0 AN: 35636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25092

East Asian (EAS) AF: 0.00 AC: 0 AN: 35582

South Asian (SAS) AF: 0.00 AC: 0 AN: 79016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4496

European-Non Finnish (NFE) AF: 0.00000557 AC: 6 AN: 1078054

Other (OTH) AF: 0.0000173 AC: 1 AN: 57730

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000896 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Parkinsonian-pyramidal syndrome (3)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.9
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
PromoterAI		0.0024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.58
Mutation Taster		=28/72	disease causing (ClinVar)

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: rs121918305; hg19: chr22-32871054;