5-171872872-C-T

Variant names:

• chr5-171872872-C-T
• rs2113763285
• NM_001378974.1:c.1340G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_001378974.1(FBXW11):​c.1340G>A​(p.Arg447Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXW11 NM_001378974.1 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.86
• Publications: 1 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: Likely_pathogenic. The variant received 7 ACMG points.

• 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.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.1340G>A	p.Arg447Lys	missense splice_region	Exon 10 of 14	NP_001365903.1	E5RGC1
	FBXW11	NM_012300.3		c.1277G>A	p.Arg426Lys	missense splice_region	Exon 9 of 13	NP_036432.2
	FBXW11	NM_001378975.1		c.1271G>A	p.Arg424Lys	missense splice_region	Exon 9 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.1340G>A	p.Arg447Lys	missense splice_region	Exon 10 of 14	ENSP00000428753.2	E5RGC1
	FBXW11	ENST00000265094.9	TSL:1	c.1277G>A	p.Arg426Lys	missense splice_region	Exon 9 of 13	ENSP00000265094.5	Q9UKB1-1
	FBXW11	ENST00000296933.10	TSL:1	c.1238G>A	p.Arg413Lys	missense splice_region	Exon 9 of 13	ENSP00000296933.6	Q9UKB1-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Neurodevelopmental, jaw, eye, and digital syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.84	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.26
Sift	Benign	0.053	T
Sift4G	Benign	0.30	T
Polyphen		0.96	D
Vest4		0.82
MutPred		0.68		Gain of ubiquitination at R426 (P = 0.0267)
MVP		0.61
MPC		2.5
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.67
gMVP		0.84
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.77		Position offset: 0

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

Other links and lift over

dbSNP: rs2113763285; hg19: chr5-171299876;