chr2-47839485-T-A

Variant names:

• chr2-47839485-T-A
• rs17036993
• NM_001190274.2:c.376A>T

Variant summary

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

The ENST00000403359.8(FBXO11):​c.376A>T​(p.Thr126Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,613,956 control chromosomes in the GnomAD database, including 281 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T126A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (144 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (137 hom.)
• Consequence: FBXO11 ENST00000403359.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 1.57
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016235709).
• BP6: Variant 2-47839485-T-A is Benign according to our data. Variant chr2-47839485-T-A is described in ClinVar as Benign. ClinVar VariationId is 134377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0765 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000403359.8. 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.376A>T	p.Thr126Ser	missense	Exon 3 of 23	NP_001177203.1
	FBXO11	NM_001374325.1		c.124A>T	p.Thr42Ser	missense	Exon 3 of 23	NP_001361254.1
	FBXO11	NM_025133.4		c.124A>T	p.Thr42Ser	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.376A>T	p.Thr126Ser	missense	Exon 3 of 23	ENSP00000384823.4
	FBXO11	ENST00000402508.5	TSL:1	c.124A>T	p.Thr42Ser	missense	Exon 3 of 23	ENSP00000385398.1
	FBXO11	ENST00000492225.5	TSL:1	n.224A>T		non_coding_transcript_exon	Exon 3 of 16

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3431 AN: 152202 Hom.: 143 Cov.: 32

Gnomad AFR AF: 0.0788

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00554 AC: 1389 AN: 250696 AF XY: 0.00400

Gnomad AFR exome AF: 0.0793

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00229 AC: 3344 AN: 1461636 Hom.: 137 Cov.: 31 AF XY: 0.00189 AC XY: 1373 AN XY: 727070

African (AFR) AF: 0.0820 AC: 2746 AN: 33470

American (AMR) AF: 0.00327 AC: 146 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.000131 AC: 146 AN: 1111966

Other (OTH) AF: 0.00470 AC: 284 AN: 60382

GnomAD4 genome AF: 0.0226 AC: 3440 AN: 152320 Hom.: 144 Cov.: 32 AF XY: 0.0218 AC XY: 1621 AN XY: 74492

African (AFR) AF: 0.0787 AC: 3272 AN: 41550

American (AMR) AF: 0.00745 AC: 114 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68036

Other (OTH) AF: 0.0180 AC: 38 AN: 2114

Alfa AF: 0.000996 Hom.: 0

Bravo AF: 0.0257

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0820 AC: 361

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00702 AC: 852

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	FBXO11-related disorder (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.83
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.029
Sift	Benign	0.93	T
Sift4G	Benign	0.73	T
Polyphen		0.038	B
Vest4		0.10
MutPred		0.17		Loss of catalytic residue at T126 (P = 0.0545)
MVP		0.43
MPC		0.33
ClinPred		0.012	T
GERP RS		1.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.030
gMVP		0.14
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17036993; hg19: chr2-48066624;