22-32493290-C-T

Variant names:

• chr22-32493290-C-T
• rs199954341
• NM_012179.4:c.1144+9C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_012179.4(FBXO7):​c.1144+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,611,864 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: FBXO7 NM_012179.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.291
• Publications: 2 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), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 22-32493290-C-T is Benign according to our data. Variant chr22-32493290-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 341317.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000986 (150/152206) while in subpopulation NFE AF = 0.00171 (116/68026). AF 95% confidence interval is 0.00145. There are 0 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.1144+9C>T		intron	N/A	NP_036311.3
	FBXO7	NM_001033024.2		c.907+9C>T		intron	N/A	NP_001028196.1
	FBXO7	NM_001257990.2		c.802+9C>T		intron	N/A	NP_001244919.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO7	ENST00000266087.12	TSL:1 MANE Select	c.1144+9C>T		intron	N/A	ENSP00000266087.7
	FBXO7	ENST00000886524.1		c.1162+9C>T		intron	N/A	ENSP00000556583.1
	FBXO7	ENST00000920428.1		c.1144+9C>T		intron	N/A	ENSP00000590487.1

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152088 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00141 AC: 355 AN: 251350 AF XY: 0.00132

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00347

Gnomad NFE exome AF: 0.00231

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00159 AC: 2328 AN: 1459658 Hom.: 4 Cov.: 29 AF XY: 0.00154 AC XY: 1116 AN XY: 726310

African (AFR) AF: 0.000180 AC: 6 AN: 33424

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86220

European-Finnish (FIN) AF: 0.00348 AC: 186 AN: 53396

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00185 AC: 2048 AN: 1110018

Other (OTH) AF: 0.00131 AC: 79 AN: 60316

GnomAD4 genome AF: 0.000986 AC: 150 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.000914 AC XY: 68 AN XY: 74420

African (AFR) AF: 0.000337 AC: 14 AN: 41518

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00171 AC: 116 AN: 68026

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.000774

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	Parkinsonian-pyramidal syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.81
PhyloP100		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs199954341; hg19: chr22-32889277;