2-47808534-A-G

Position:

• chr2-47808534-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001190274.2(FBXO11):​c.2556-107T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 898,162 control chromosomes in the GnomAD database, including 75,298 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 0.36 (10590 hom., cov: 33)
  • Exomes 𝑓: 0.41 (64708 hom.)
• Consequence: FBXO11 NM_001190274.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60

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]

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

FBXO11 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO11	NM_001190274.2	c.2556-107T>C		intron_variant		ENST00000403359.8	NP_001177203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO11	ENST00000403359.8	c.2556-107T>C		intron_variant		1	NM_001190274.2	ENSP00000384823.4

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54182 AN: 152052 Hom.: 10590 Cov.: 33

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.378

GnomAD4 exome AF: 0.405 AC: 302474 AN: 745992 Hom.: 64708 Cov.: 10 AF XY: 0.408 AC XY: 153229 AN XY: 375380

Gnomad4 AFR exome AF: 0.181

Gnomad4 AMR exome AF: 0.486

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.637

Gnomad4 SAS exome AF: 0.470

Gnomad4 FIN exome AF: 0.341

Gnomad4 NFE exome AF: 0.397

Gnomad4 OTH exome AF: 0.396

GnomAD4 genome AF: 0.356 AC: 54172 AN: 152170 Hom.: 10590 Cov.: 33 AF XY: 0.359 AC XY: 26738 AN XY: 74380

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.454

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.682

Gnomad4 SAS AF: 0.496

Gnomad4 FIN AF: 0.336

Gnomad4 NFE AF: 0.396

Gnomad4 OTH AF: 0.375

Alfa AF: 0.387 Hom.: 11539

Bravo AF: 0.361

Asia WGS AF: 0.538 AC: 1869 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.75
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2710163; hg19: chr2-48035673;