chr7-5500972-C-A

Variant names:

• chr7-5500972-C-A
• rs778622022
• NM_024963.6:c.1297G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024963.6(FBXL18):​c.1297G>T​(p.Asp433Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,383,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D433N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBXL18 NM_024963.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.27
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35208172).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL18	NM_024963.6	c.1297G>T	p.Asp433Tyr	missense_variant	Exon 3 of 5	ENST00000382368.8	NP_079239.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL18	ENST00000382368.8	c.1297G>T	p.Asp433Tyr	missense_variant	Exon 3 of 5	5	NM_024963.6	ENSP00000371805.3
FBXL18	ENST00000458142.1	c.946G>T	p.Asp316Tyr	missense_variant	Exon 1 of 3	2		ENSP00000405896.1
FBXL18	ENST00000415009.5	n.1297G>T		non_coding_transcript_exon_variant	Exon 3 of 7	2		ENSP00000415064.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000637 AC: 1 AN: 157090 AF XY: 0.0000115

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: 0.0000136

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1383500 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 682684

African (AFR) AF: 0.00 AC: 0 AN: 30954

American (AMR) AF: 0.00 AC: 0 AN: 30764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21718

East Asian (EAS) AF: 0.00 AC: 0 AN: 38624

South Asian (SAS) AF: 0.00 AC: 0 AN: 74406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5448

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080242

Other (OTH) AF: 0.0000175 AC: 1 AN: 57218

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000865 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Uncertain	0.98
Eigen	Benign	0.12
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.18
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.014	D
Polyphen		0.90	P
Vest4		0.35
MutPred		0.15		Loss of solvent accessibility (P = 0.0052);
MVP		0.73
MPC		1.6
ClinPred		0.59	D
GERP RS		4.2
gMVP		0.50
Mutation Taster		=91/9	polymorphism

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: rs778622022; hg19: chr7-5540603; COSMIC: COSV101212040;