chr7-5500923-C-T

Variant names:

• chr7-5500923-C-T
• rs1038387212
• NM_024963.6:c.1346G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024963.6(FBXL18):​c.1346G>A​(p.Gly449Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,412,592 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G449V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBXL18 NM_024963.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.63
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL18	NM_024963.6	c.1346G>A	p.Gly449Asp	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.1346G>A	p.Gly449Asp	missense_variant	Exon 3 of 5	5	NM_024963.6	ENSP00000371805.3
FBXL18	ENST00000458142.1	c.995G>A	p.Gly332Asp	missense_variant	Exon 1 of 3	2		ENSP00000405896.1
FBXL18	ENST00000415009.5	n.1346G>A		non_coding_transcript_exon_variant	Exon 3 of 7	2		ENSP00000415064.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000519 AC: 1 AN: 192554 AF XY: 0.00000942

Gnomad AFR exome AF: 0.0000839

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: 0.00000142 AC: 2 AN: 1412592 Hom.: 0 Cov.: 30 AF XY: 0.00000286 AC XY: 2 AN XY: 698138

African (AFR) AF: 0.0000312 AC: 1 AN: 32076

American (AMR) AF: 0.00 AC: 0 AN: 36630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23420

East Asian (EAS) AF: 0.00 AC: 0 AN: 39016

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5562

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088406

Other (OTH) AF: 0.00 AC: 0 AN: 58176

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;T
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.9	L;.
PhyloP100		3.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.19
Sift	Uncertain	0.029	D;.
Sift4G	Uncertain	0.053	T;.
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.23		Loss of methylation at R446 (P = 0.06);.;
MVP		0.82
MPC		1.7
ClinPred		0.69	D
GERP RS		5.4
gMVP		0.58
Mutation Taster		=75/25	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: rs1038387212; hg19: chr7-5540554;