rs765326368

Variant names:

• chr7-5500935-G-A
• rs765326368
• NM_024963.6:c.1334C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-5500935-G-A
• chr7-5500935-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024963.6(FBXL18):​c.1334C>T​(p.Pro445Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000322 in 1,551,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. P445R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: FBXL18 NM_024963.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.13
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16358316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL18	NM_024963.6	c.1334C>T	p.Pro445Leu	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.1334C>T	p.Pro445Leu	missense_variant	Exon 3 of 5	5	NM_024963.6	ENSP00000371805.3
FBXL18	ENST00000458142.1	c.983C>T	p.Pro328Leu	missense_variant	Exon 1 of 3	2		ENSP00000405896.1
FBXL18	ENST00000415009.5	n.1334C>T		non_coding_transcript_exon_variant	Exon 3 of 7	2		ENSP00000415064.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000575 AC: 1 AN: 173802 AF XY: 0.0000104

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: 0.0000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1399562 Hom.: 0 Cov.: 30 AF XY: 0.00000434 AC XY: 3 AN XY: 690956

African (AFR) AF: 0.0000316 AC: 1 AN: 31612

American (AMR) AF: 0.00 AC: 0 AN: 33670

Ashkenazi Jewish (ASJ) AF: 0.0000440 AC: 1 AN: 22702

East Asian (EAS) AF: 0.00 AC: 0 AN: 38852

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5516

European-Non Finnish (NFE) AF: 9.23e-7 AC: 1 AN: 1083852

Other (OTH) AF: 0.00 AC: 0 AN: 57686

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74360

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000170 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.73
DEOGEN2	Benign	0.087	.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L;.
PhyloP100		3.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.088
Sift	Benign	0.98	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0050	B;.
Vest4		0.25
MutPred		0.42		Gain of helix (P = 0.0022);.;
MVP		0.68
MPC		0.73
ClinPred		0.092	T
GERP RS		4.5
gMVP		0.44
Mutation Taster		=82/18	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: rs765326368; hg19: chr7-5540566;