7-5491312-C-A

Variant names:

• chr7-5491312-C-A
• rs1200271432
• NM_024963.6:c.1919G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024963.6(FBXL18):​c.1919G>T​(p.Cys640Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,459,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: FBXL18 NM_024963.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80
• Publications: 0 publications found

Genes affected

FBXL18 (HGNC:21874): (F-box and leucine rich repeat protein 18) The protein encoded by this gene is a member of a family of proteins that contain an approximately 40-amino acid F-box motif. This motif is important for interaction with SKP1 and for targeting some proteins for degradation. The encoded protein has been shown to control the cellular level of FBXL7, a protein that induces mitotic arrest, by targeting it for polyubiquitylation and proteasomal degradation. Members of the F-box protein family, such as FBXL18, are characterized by an approximately 40-amino acid F-box motif. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024963.6. 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
	FBXL18	NM_024963.6	MANE Select	c.1919G>T	p.Cys640Phe	missense	Exon 4 of 5	NP_079239.3
	FBXL18	NM_001321213.2		c.1919G>T	p.Cys640Phe	missense	Exon 4 of 5	NP_001308142.1	Q96ME1-5
	FBXL18	NM_001363441.2		c.1919G>T	p.Cys640Phe	missense	Exon 4 of 5	NP_001350370.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL18	ENST00000382368.8	TSL:5 MANE Select	c.1919G>T	p.Cys640Phe	missense	Exon 4 of 5	ENSP00000371805.3	Q96ME1-4
	FBXL18	ENST00000458142.1	TSL:2	c.1568G>T	p.Cys523Phe	missense	Exon 2 of 3	ENSP00000405896.1	A0A994ENR3
	FBXL18	ENST00000948868.1		c.1700G>T	p.Cys567Phe	missense	Exon 3 of 4	ENSP00000618927.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 242512 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459620 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726076

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111574

Other (OTH) AF: 0.00 AC: 0 AN: 60232

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	2.0	M
PhyloP100		5.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.082	T
Polyphen		0.85	P
Vest4		0.81
MutPred		0.80		Loss of catalytic residue at L641 (P = 0.0233)
MVP		0.81
MPC		1.4
ClinPred		0.99	D
GERP RS		4.0
gMVP		0.89
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1200271432; hg19: chr7-5530943;