rs200771165

chr2-47809222-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 1P and 18B. PP2 BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001190274.2(FBXO11):c.2491A>G(p.Ser831Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000307 in 1,606,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: FBXO11 NM_001190274.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2 O:1
• Conservation: PhyloP100: 5.99

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FBXO11
• BP4: Computational evidence support a benign effect (MetaRNN=0.24323764).
• BP6: Variant 2-47809222-T-C is Benign according to our data. Variant chr2-47809222-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 134376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47809222-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000243 (37/152352) while in subpopulation NFE AF= 0.000367 (25/68036). AF 95% confidence interval is 0.000255. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXO11	NM_001190274.2	c.2491A>G	p.Ser831Gly	missense_variant	21/23	ENST00000403359.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXO11	ENST00000403359.8	c.2491A>G	p.Ser831Gly	missense_variant	21/23	1	NM_001190274.2

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000225 AC: 56 AN: 248392 Hom.: 0 AF XY: 0.000216 AC XY: 29 AN XY: 134166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.000134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000381

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000314 AC: 457 AN: 1454460 Hom.: 0 Cov.: 27 AF XY: 0.000316 AC XY: 229 AN XY: 723812

Gnomad4 AFR exome AF: 0.000602

Gnomad4 AMR exome AF: 0.000181

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000301

Gnomad4 OTH exome AF: 0.000781

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74504

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000449 Hom.: 0

Bravo AF: 0.000249

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000877

EpiControl AF: 0.000535

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder Uncertain:1

Uncertain significance, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

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- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.16
Sift	Benign	0.30	T;T
Sift4G	Benign	0.32	T;T
Vest4		0.46
MVP		0.64
MPC		1.3
ClinPred		0.059	T
GERP RS		5.0
Varity_R		0.26
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs200771165; hg19: chr2-48036361; COSMIC: COSV52278411; COSMIC: COSV52278411;