16-696946-C-T

Variant names:

• chr16-696946-C-T
• rs2040016970
• NM_153350.4:c.460G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_153350.4(FBXL16):​c.460G>A​(p.Glu154Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,451,626 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: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: FBXL16 NM_153350.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.42

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37726513).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL16	NM_153350.4	c.460G>A	p.Glu154Lys	missense_variant	Exon 2 of 6	ENST00000397621.6	NP_699181.2
FBXL16	XM_047433646.1	c.460G>A	p.Glu154Lys	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.460G>A	p.Glu154Lys	missense_variant	Exon 2 of 6	5	NM_153350.4	ENSP00000380746.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1451626 Hom.: 0 Cov.: 56 AF XY: 0.00000277 AC XY: 2 AN XY: 721964

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: 0.0000237

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.460G>A (p.E154K) alteration is located in exon 2 (coding exon 1) of the FBXL16 gene. This alteration results from a G to A substitution at nucleotide position 460, causing the glutamic acid (E) at amino acid position 154 to be replaced by a lysine (K). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.23
Sift	Benign	0.20	T;T
Sift4G	Benign	0.10	T;T
Polyphen		0.38	B;B
Vest4		0.65
MutPred		0.52		Gain of ubiquitination at E154 (P = 0.0238);Gain of ubiquitination at E154 (P = 0.0238);
MVP		0.093
MPC		0.60
ClinPred		0.84	D
GERP RS		4.2
Varity_R		0.17
gMVP		0.56

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: rs2040016970; hg19: chr16-746946;