2-47813146-A-C

Variant names:

• chr2-47813146-A-C
• rs3732191
• NM_001190274.2:c.2227+88T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001190274.2(FBXO11):​c.2227+88T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0688 in 1,300,850 control chromosomes in the GnomAD database, including 3,549 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.055 (296 hom., cov: 32)
  • Exomes 𝑓: 0.071 (3253 hom.)
• Consequence: FBXO11 NM_001190274.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.217
• Publications: 10 publications found

Genes affected

FBXO11 (HGNC:13590): (F-box protein 11) 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 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. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

FBXO11 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO11	NM_001190274.2	c.2227+88T>G		intron_variant	Intron 18 of 22	ENST00000403359.8	NP_001177203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO11	ENST00000403359.8	c.2227+88T>G		intron_variant	Intron 18 of 22	1	NM_001190274.2	ENSP00000384823.4

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8351 AN: 152106 Hom.: 295 Cov.: 32

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0916

Gnomad ASJ AF: 0.0809

Gnomad EAS AF: 0.0450

Gnomad SAS AF: 0.0441

Gnomad FIN AF: 0.0597

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0693

Gnomad OTH AF: 0.0516

GnomAD2 exomes AF: 0.0687 AC: 17166 AN: 249958 AF XY: 0.0659

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.0786

Gnomad EAS exome AF: 0.0500

Gnomad FIN exome AF: 0.0593

Gnomad NFE exome AF: 0.0722

Gnomad OTH exome AF: 0.0671

GnomAD4 exome AF: 0.0707 AC: 81193 AN: 1148626 Hom.: 3253 Cov.: 16 AF XY: 0.0692 AC XY: 40655 AN XY: 587194

African (AFR) AF: 0.0127 AC: 341 AN: 26768

American (AMR) AF: 0.118 AC: 5214 AN: 44168

Ashkenazi Jewish (ASJ) AF: 0.0779 AC: 1872 AN: 24046

East Asian (EAS) AF: 0.0332 AC: 1258 AN: 37888

South Asian (SAS) AF: 0.0388 AC: 3089 AN: 79696

European-Finnish (FIN) AF: 0.0574 AC: 3029 AN: 52804

Middle Eastern (MID) AF: 0.0545 AC: 283 AN: 5196

European-Non Finnish (NFE) AF: 0.0759 AC: 62832 AN: 828258

Other (OTH) AF: 0.0658 AC: 3275 AN: 49802

GnomAD4 genome AF: 0.0549 AC: 8359 AN: 152224 Hom.: 296 Cov.: 32 AF XY: 0.0540 AC XY: 4023 AN XY: 74432

African (AFR) AF: 0.0157 AC: 653 AN: 41552

American (AMR) AF: 0.0921 AC: 1407 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0809 AC: 281 AN: 3472

East Asian (EAS) AF: 0.0449 AC: 233 AN: 5184

South Asian (SAS) AF: 0.0441 AC: 213 AN: 4826

European-Finnish (FIN) AF: 0.0597 AC: 631 AN: 10574

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0694 AC: 4717 AN: 68016

Other (OTH) AF: 0.0516 AC: 109 AN: 2114

Alfa AF: 0.0643 Hom.: 696

Bravo AF: 0.0572

Asia WGS AF: 0.0430 AC: 149 AN: 3472

EpiCase AF: 0.0694

EpiControl AF: 0.0691

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3732191; hg19: chr2-48040285; COSMIC: COSV52287408; COSMIC: COSV52287408;