rs192327462

chr22-32475133-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_012179.4(FBXO7):c.122+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,540,668 control chromosomes in the GnomAD database, including 28 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 0.0039 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (25 hom.)
• Consequence: FBXO7 NM_012179.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0480

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 22-32475133-G-A is Benign according to our data. Variant chr22-32475133-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 341307.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr22-32475133-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00393 (598/152318) while in subpopulation NFE AF= 0.00706 (480/68012). AF 95% confidence interval is 0.00654. There are 3 homozygotes in gnomad4. There are 260 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXO7	NM_012179.4	c.122+9G>A		intron_variant		ENST00000266087.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXO7	ENST00000266087.12	c.122+9G>A		intron_variant		1	NM_012179.4	P2
FBXO7	ENST00000420700.5	c.122+9G>A		intron_variant, NMD_transcript_variant		5
FBXO7	ENST00000425028.5	c.122+9G>A		intron_variant, NMD_transcript_variant		5
FBXO7	ENST00000492535.1	n.110+9G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 599 AN: 152210 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00706

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00311 AC: 425 AN: 136722 Hom.: 0 AF XY: 0.00308 AC XY: 228 AN XY: 74050

Gnomad AFR exome AF: 0.000548

Gnomad AMR exome AF: 0.000747

Gnomad ASJ exome AF: 0.00138

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000501

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00706

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00563 AC: 7820 AN: 1388350 Hom.: 25 Cov.: 32 AF XY: 0.00546 AC XY: 3736 AN XY: 684556

Gnomad4 AFR exome AF: 0.000856

Gnomad4 AMR exome AF: 0.000792

Gnomad4 ASJ exome AF: 0.00193

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.00185

Gnomad4 NFE exome AF: 0.00686

Gnomad4 OTH exome AF: 0.00353

GnomAD4 genome AF: 0.00393 AC: 598 AN: 152318 Hom.: 3 Cov.: 33 AF XY: 0.00349 AC XY: 260 AN XY: 74474

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00103

Gnomad4 NFE AF: 0.00706

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00507 Hom.: 1

Bravo AF: 0.00384

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Parkinsonian-pyramidal syndrome Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 19, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 03, 2017

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

FBXO7: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	6.9
Dann	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs192327462; hg19: chr22-32871120;