rs2113754835

Variant names:

• chr5-171870806-C-T
• rs2113754835
• NM_001378974.1:c.1393G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_001378974.1(FBXW11):​c.1393G>A​(p.Glu465Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXW11 NM_001378974.1 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.86
• Publications: 0 publications found

Genes affected

FBXW11 (HGNC:13607): (F-box and WD repeat domain containing 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 Fbws class and, in addition to an F-box, contains multiple WD40 repeats. This gene contains at least 14 exons, and its alternative splicing generates 3 transcript variants diverging at the presence/absence of two alternate exons. [provided by RefSeq, Jul 2008]

FBXW11 Gene-Disease associations (from GenCC):

• neurodevelopmental, jaw, eye, and digital syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001378974.1
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.9567 (above the threshold of 3.09). Trascript score misZ: 5.0303 (above the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental, jaw, eye, and digital syndrome, syndromic intellectual disability.
• PP5: Variant 5-171870806-C-T is Pathogenic according to our data. Variant chr5-171870806-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1064510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378974.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW11	NM_001378974.1	MANE Select	c.1393G>A	p.Glu465Lys	missense	Exon 11 of 14	NP_001365903.1	E5RGC1
	FBXW11	NM_012300.3		c.1330G>A	p.Glu444Lys	missense	Exon 10 of 13	NP_036432.2
	FBXW11	NM_001378975.1		c.1324G>A	p.Glu442Lys	missense	Exon 10 of 13	NP_001365904.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW11	ENST00000517395.6	TSL:3 MANE Select	c.1393G>A	p.Glu465Lys	missense	Exon 11 of 14	ENSP00000428753.2	E5RGC1
	FBXW11	ENST00000265094.9	TSL:1	c.1330G>A	p.Glu444Lys	missense	Exon 10 of 13	ENSP00000265094.5	Q9UKB1-1
	FBXW11	ENST00000296933.10	TSL:1	c.1291G>A	p.Glu431Lys	missense	Exon 10 of 13	ENSP00000296933.6	Q9UKB1-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Neurodevelopmental, jaw, eye, and digital syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.025	N
PhyloP100		7.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.011	D
Sift4G	Benign	0.19	T
Polyphen		0.89	P
Vest4		0.81
MutPred		0.51		Gain of MoRF binding (P = 0.0068)
MVP		0.72
MPC		2.6
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.80
gMVP		0.85
Mutation Taster		=1/99	disease causing

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: rs2113754835; hg19: chr5-171297810;