chr5-171870795-TC-CA

Variant names:

• chr5-171870795-TC-CA
• NM_001378974.1:c.1403_1404delGAinsTG
• FBXW11 p.Arg468Leu

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1 PM5 PP2 PP3

The NM_001378974.1(FBXW11):​c.1403_1404delGAinsTG​(p.Arg468Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R468Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXW11 NM_001378974.1 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_001378974.1 (FBXW11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-171870796-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1064511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 syndromic intellectual disability, neurodevelopmental, jaw, eye, and digital syndrome.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1403_1404delGAinsTG	p.Arg468Leu	missense	N/A	NP_001365903.1	E5RGC1
	FBXW11	NM_012300.3		c.1340_1341delGAinsTG	p.Arg447Leu	missense	N/A	NP_036432.2
	FBXW11	NM_001378975.1		c.1334_1335delGAinsTG	p.Arg445Leu	missense	N/A	NP_001365904.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW11	ENST00000517395.6	TSL:3 MANE Select	c.1403_1404delGAinsTG	p.Arg468Leu	missense	N/A	ENSP00000428753.2	E5RGC1
	FBXW11	ENST00000265094.9	TSL:1	c.1340_1341delGAinsTG	p.Arg447Leu	missense	N/A	ENSP00000265094.5	Q9UKB1-1
	FBXW11	ENST00000296933.10	TSL:1	c.1301_1302delGAinsTG	p.Arg434Leu	missense	N/A	ENSP00000296933.6	Q9UKB1-3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-171297799;