Genetic Variant FBXL16:p.Arg202Cys (chr16-696802-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_153350.4(FBXL16):c.604C>T(p.Arg202Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000536 in 1,399,786 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000050 ( 1 hom. )

Consequence

FBXL16
NM_153350.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.34

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.28349233).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL16	NM_153350.4 link	c.604C>T	p.Arg202Cys	missense_variant	Exon 2 of 6	ENST00000397621.6	NP_699181.2	Q8N461-1
FBXL16	XM_047433646.1 link	c.604C>T	p.Arg202Cys	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 link	c.604C>T	p.Arg202Cys	missense_variant	Exon 2 of 6	5	NM_153350.4	ENSP00000380746.1		Q8N461-1

Frequencies

GnomAD3 genomes

AF:

0.000367

AC:

AN:

16356

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000759

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:

0.000635

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000859

AC:

AN:

197806

Hom.:

AF XY:

0.0000746

AC XY:

AN XY:

107232

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000273

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000698

Gnomad SAS exome

AF:

0.000246

Gnomad FIN exome

AF:

0.0000548

Gnomad NFE exome

AF:

0.0000213

Gnomad OTH exome

AF:

0.000211

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1383430

Hom.:

Cov.:

AF XY:

0.0000570

AC XY:

AN XY:

683680

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000410

Gnomad4 SAS exome

AF:

0.000245

Gnomad4 FIN exome

AF:

0.0000210

Gnomad4 NFE exome

AF:

0.0000214

Gnomad4 OTH exome

AF:

0.0000702

GnomAD4 genome

AF:

0.000367

AC:

AN:

16356

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

8272

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000759

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000635

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000121

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000578

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.604C>T (p.R202C) 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 604, causing the arginine (R) at amino acid position 202 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

Uncertain

0.52

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.018

T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.052

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.94

.;D

M_CAP

Benign

0.046

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.63

N;N

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

3.1

N;N

REVEL

Benign

0.23

Sift

Benign

0.12

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.090

B;B

Vest4

0.94

MutPred

0.55

Gain of methylation at K201 (P = 0.0168);Gain of methylation at K201 (P = 0.0168);

MVP

0.14

MPC

2.1

ClinPred

0.027

GERP RS

3.9

Varity_R

0.13

gMVP

0.90

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