Genetic Variant FBXL16:p.Ile478Val (chr16-694283-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_153350.4(FBXL16):c.1432A>G(p.Ile478Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000753 in 1,421,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

FBXL16
NM_153350.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.81

Variant links:

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]

FBXL16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13245189).

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL16	NM_153350.4 link	c.1432A>G	p.Ile478Val	missense_variant	Exon 6 of 6	ENST00000397621.6	NP_699181.2	Q8N461-1
FBXL16	XM_047433646.1 link	c.1432A>G	p.Ile478Val	missense_variant	Exon 6 of 6		XP_047289602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBXL16	ENST00000397621.6 link	c.1432A>G	p.Ile478Val	missense_variant	Exon 6 of 6	5	NM_153350.4	ENSP00000380746.1	Q8N461-1
FBXL16	ENST00000562648.2 link	n.746A>G		non_coding_transcript_exon_variant	Exon 3 of 3	1
FBXL16	ENST00000562563.1 link	c.796A>G	p.Ile266Val	missense_variant	Exon 4 of 4	2		ENSP00000455217.1	Q8N461-2

Frequencies

GnomAD3 genomes

AF:

0.0000856

AC:

AN:

151858

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000248

AC:

AN:

120930

Hom.:

AF XY:

0.0000292

AC XY:

AN XY:

68604

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000483

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000740

AC:

AN:

1269814

Hom.:

Cov.:

AF XY:

0.0000759

AC XY:

AN XY:

619240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000396

Gnomad4 AMR exome

AF:

0.0000533

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000209

Gnomad4 NFE exome

AF:

0.0000845

Gnomad4 OTH exome

AF:

0.0000973

GnomAD4 genome

AF:

0.0000856

AC:

AN:

151858

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000121

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000243

AC:

ExAC

AF:

0.0000422

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1432A>G (p.I478V) alteration is located in exon 6 (coding exon 5) of the FBXL16 gene. This alteration results from a A to G substitution at nucleotide position 1432, causing the isoleucine (I) at amino acid position 478 to be replaced by a valine (V). 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

0.15

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.035

T;T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.62

.;T;T

M_CAP

Benign

0.085

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.71

N;N;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.53

N;N;N

REVEL

Benign

0.076

Sift

Benign

0.17

T;T;T

Sift4G

Benign

0.25

T;T;T

Polyphen

0.46

P;P;.

Vest4

0.13

MVP

0.043

MPC

0.53

ClinPred

0.19

GERP RS

1.9

Varity_R

0.065

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over