16-697273-G-A

Variant names:

• chr16-697273-G-A
• rs1313063809
• NM_153350.4:c.133C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153350.4(FBXL16):​c.133C>T​(p.Arg45Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000292 in 1,369,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: FBXL16 NM_153350.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.30

Genes affected

FBXL16 (HGNC:14150): (F-box and leucine rich repeat protein 16) Members of the F-box protein family, such as FBXL16, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.381574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL16	NM_153350.4	c.133C>T	p.Arg45Cys	missense_variant	Exon 2 of 6	ENST00000397621.6	NP_699181.2
FBXL16	XM_047433646.1	c.133C>T	p.Arg45Cys	missense_variant	Exon 2 of 6		XP_047289602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL16	ENST00000397621.6	c.133C>T	p.Arg45Cys	missense_variant	Exon 2 of 6	5	NM_153350.4	ENSP00000380746.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000292 AC: 4 AN: 1369338 Hom.: 0 Cov.: 39 AF XY: 0.00000445 AC XY: 3 AN XY: 674368

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000280

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.133C>T (p.R45C) alteration is located in exon 2 (coding exon 1) of the FBXL16 gene. This alteration results from a C to T substitution at nucleotide position 133, causing the arginine (R) at amino acid position 45 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.061	T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.039	D;D
Polyphen		0.99	D;D
Vest4		0.48
MutPred		0.22		Gain of ubiquitination at K43 (P = 0.0282);Gain of ubiquitination at K43 (P = 0.0282);
MVP		0.068
MPC		1.7
ClinPred		0.85	D
GERP RS		4.3
Varity_R		0.31
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs1313063809; hg19: chr16-747273;