2-47839447-T-A

Variant names:

• chr2-47839447-T-A
• rs1553342109
• NM_001190274.2:c.414A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PM5 PP5 BP4

The NM_001190274.2(FBXO11):​c.414A>T​(p.Arg138Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXO11 NM_001190274.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 3.29
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47839449-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1329867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 2-47839447-T-A is Pathogenic according to our data. Variant chr2-47839447-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 559601.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1753524). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190274.2. 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
	FBXO11	NM_001190274.2	MANE Select	c.414A>T	p.Arg138Ser	missense	Exon 3 of 23	NP_001177203.1
	FBXO11	NM_001374325.1		c.162A>T	p.Arg54Ser	missense	Exon 3 of 23	NP_001361254.1
	FBXO11	NM_025133.4		c.162A>T	p.Arg54Ser	missense	Exon 3 of 23	NP_079409.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO11	ENST00000403359.8	TSL:1 MANE Select	c.414A>T	p.Arg138Ser	missense	Exon 3 of 23	ENSP00000384823.4
	FBXO11	ENST00000402508.5	TSL:1	c.162A>T	p.Arg54Ser	missense	Exon 3 of 23	ENSP00000385398.1
	FBXO11	ENST00000492225.5	TSL:1	n.262A>T		non_coding_transcript_exon	Exon 3 of 16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities Pathogenic:1

Aug 17, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Neurodevelopmental disorder Pathogenic:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.31
Sift	Benign	0.11	T
Sift4G	Benign	0.91	T
Polyphen		0.038	B
Vest4		0.77
MutPred		0.33		Gain of phosphorylation at R138 (P = 0.0137)
MVP		0.87
MPC		0.42
ClinPred		0.42	T
GERP RS		2.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.34
gMVP		0.54
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs1553342109; hg19: chr2-48066586;