2-47810771-A-G

Variant names:

• chr2-47810771-A-G
• rs3771285
• NM_001190274.2:c.2228-345T>C

Variant summary

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

The NM_001190274.2(FBXO11):​c.2228-345T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00859 in 171,986 control chromosomes in the GnomAD database, including 36 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 0.0084 (32 hom., cov: 33)
  • Exomes 𝑓: 0.0099 (4 hom.)
• Consequence: FBXO11 NM_001190274.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25
• Publications: 2 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=-0.82).
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO11	NM_001190274.2	c.2228-345T>C		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.2228-345T>C		intron_variant	Intron 18 of 22	1	NM_001190274.2	ENSP00000384823.4

Frequencies

GnomAD3 genomes AF: 0.00840 AC: 1278 AN: 152066 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0244

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.0450

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0437

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00864

GnomAD4 exome AF: 0.00990 AC: 196 AN: 19802 Hom.: 4 Cov.: 0 AF XY: 0.00942 AC XY: 96 AN XY: 10190

African (AFR) AF: 0.00120 AC: 1 AN: 830

American (AMR) AF: 0.0307 AC: 19 AN: 618

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 13 AN: 858

East Asian (EAS) AF: 0.0678 AC: 78 AN: 1150

South Asian (SAS) AF: 0.00197 AC: 1 AN: 508

European-Finnish (FIN) AF: 0.0556 AC: 48 AN: 864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 96

European-Non Finnish (NFE) AF: 0.00155 AC: 21 AN: 13524

Other (OTH) AF: 0.0111 AC: 15 AN: 1354

GnomAD4 genome AF: 0.00842 AC: 1281 AN: 152184 Hom.: 32 Cov.: 33 AF XY: 0.0103 AC XY: 769 AN XY: 74398

African (AFR) AF: 0.00118 AC: 49 AN: 41514

American (AMR) AF: 0.0246 AC: 376 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3470

East Asian (EAS) AF: 0.0449 AC: 233 AN: 5188

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.0437 AC: 463 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00168 AC: 114 AN: 67986

Other (OTH) AF: 0.00855 AC: 18 AN: 2106

Alfa AF: 0.00341 Hom.: 0

Bravo AF: 0.00882

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.7
DANN	Benign	0.57
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs3771285; hg19: chr2-48037910;