chr22-32475396-T-G

Variant names:

• chr22-32475396-T-G
• rs8137714
• NM_012179.4:c.122+272T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012179.4(FBXO7):​c.122+272T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,610,858 control chromosomes in the GnomAD database, including 33,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2743 hom., cov: 33)
  • Exomes 𝑓: 0.20 (31069 hom.)
• Consequence: FBXO7 NM_012179.4 intron
• Scores: Splicing: ADA: 0.00005058
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.301
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020529926).
• BP6: Variant 22-32475396-T-G is Benign according to our data. Variant chr22-32475396-T-G is described in ClinVar as Benign. ClinVar VariationId is 518326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO7	NM_012179.4	MANE Select	c.122+272T>G		intron	N/A	NP_036311.3
	FBXO7	NM_001033024.2		c.35T>G	p.Leu12Arg	missense splice_region	Exon 1 of 9	NP_001028196.1
	FBXO7	NM_001257990.2		c.-223T>G		splice_region	Exon 1 of 9	NP_001244919.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO7	ENST00000266087.12	TSL:1 MANE Select	c.122+272T>G		intron	N/A	ENSP00000266087.7
	FBXO7	ENST00000452138.3	TSL:2	c.35T>G	p.Leu12Arg	missense splice_region	Exon 1 of 9	ENSP00000388547.2
	FBXO7	ENST00000397426.5	TSL:2	c.-223T>G		splice_region	Exon 1 of 9	ENSP00000380571.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28782 AN: 152060 Hom.: 2739 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.190 AC: 45980 AN: 241456 AF XY: 0.189

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.141

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.204 AC: 297767 AN: 1458680 Hom.: 31069 Cov.: 36 AF XY: 0.203 AC XY: 147070 AN XY: 725690

African (AFR) AF: 0.142 AC: 4704 AN: 33042

American (AMR) AF: 0.200 AC: 8925 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 6633 AN: 26060

East Asian (EAS) AF: 0.187 AC: 7368 AN: 39426

South Asian (SAS) AF: 0.132 AC: 11367 AN: 85796

European-Finnish (FIN) AF: 0.219 AC: 11552 AN: 52856

Middle Eastern (MID) AF: 0.244 AC: 1402 AN: 5752

European-Non Finnish (NFE) AF: 0.210 AC: 233791 AN: 1110950

Other (OTH) AF: 0.200 AC: 12025 AN: 60266

GnomAD4 genome AF: 0.189 AC: 28800 AN: 152178 Hom.: 2743 Cov.: 33 AF XY: 0.190 AC XY: 14107 AN XY: 74396

African (AFR) AF: 0.146 AC: 6075 AN: 41532

American (AMR) AF: 0.206 AC: 3150 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 887 AN: 3468

East Asian (EAS) AF: 0.156 AC: 806 AN: 5162

South Asian (SAS) AF: 0.126 AC: 608 AN: 4820

European-Finnish (FIN) AF: 0.235 AC: 2488 AN: 10588

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14209 AN: 67988

Other (OTH) AF: 0.186 AC: 392 AN: 2112

Alfa AF: 0.200 Hom.: 7470

Bravo AF: 0.186

TwinsUK AF: 0.212 AC: 785

ALSPAC AF: 0.216 AC: 833

ESP6500AA AF: 0.148 AC: 537

ESP6500EA AF: 0.205 AC: 1668

ExAC AF: 0.184 AC: 22264

Asia WGS AF: 0.130 AC: 453 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Parkinsonian-pyramidal syndrome Benign:2

Mar 28, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Aug 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.1
DANN	Benign	0.51
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.30
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.074
Sift	Benign	0.26	T
Sift4G	Benign	0.77	T
Polyphen		0.0010	B
Vest4		0.035
ClinPred		0.0020	T
GERP RS		-6.1
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.0020
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: rs8137714; hg19: chr22-32871383; COSMIC: COSV56678147; COSMIC: COSV56678147;