rs61752254

Variant names:

• chr22-32485115-C-T
• rs61752254
• NM_012179.4:c.693C>T
• FBXO7 p.Ser231Ser

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_012179.4(FBXO7):​c.693C>T​(p.Ser231Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00441 in 1,614,128 control chromosomes in the GnomAD database, including 13 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 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (12 hom.)
• Consequence: FBXO7 NM_012179.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -5.91
• Publications: 4 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 22-32485115-C-T is Benign according to our data. Variant chr22-32485115-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 341312.
• BP7: Synonymous conserved (PhyloP=-5.91 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0028 (426/152260) while in subpopulation NFE AF = 0.00481 (327/68014). AF 95% confidence interval is 0.00438. There are 1 homozygotes in GnomAd4. There are 187 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.693C>T	p.Ser231Ser	synonymous	Exon 4 of 9	NP_036311.3
	FBXO7	NM_001033024.2		c.456C>T	p.Ser152Ser	synonymous	Exon 4 of 9	NP_001028196.1	Q9Y3I1-2
	FBXO7	NM_001257990.2		c.351C>T	p.Ser117Ser	synonymous	Exon 4 of 9	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.693C>T	p.Ser231Ser	synonymous	Exon 4 of 9	ENSP00000266087.7	Q9Y3I1-1
	FBXO7	ENST00000886524.1		c.693C>T	p.Ser231Ser	synonymous	Exon 4 of 10	ENSP00000556583.1
	FBXO7	ENST00000920428.1		c.693C>T	p.Ser231Ser	synonymous	Exon 4 of 9	ENSP00000590487.1

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 426 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00481

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00285 AC: 716 AN: 251442 AF XY: 0.00280

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00492

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00458 AC: 6695 AN: 1461868 Hom.: 12 Cov.: 31 AF XY: 0.00451 AC XY: 3281 AN XY: 727236

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.000760 AC: 34 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00159 AC: 137 AN: 86258

European-Finnish (FIN) AF: 0.00234 AC: 125 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00552 AC: 6143 AN: 1111996

Other (OTH) AF: 0.00374 AC: 226 AN: 60394

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74432

African (AFR) AF: 0.00101 AC: 42 AN: 41564

American (AMR) AF: 0.000850 AC: 13 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

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

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4824

European-Finnish (FIN) AF: 0.00255 AC: 27 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00481 AC: 327 AN: 68014

Other (OTH) AF: 0.00238 AC: 5 AN: 2104

Alfa AF: 0.00470 Hom.: 1

Bravo AF: 0.00281

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00507

EpiControl AF: 0.00415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Parkinsonian-pyramidal syndrome (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	FBXO7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.19
DANN	Benign	0.56
PhyloP100		-5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61752254;

hg19: chr22-32881102;