Genetic Variant FBXO48:p.Arg102Lys (chr2-68464841-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001024680.3(FBXO48):c.305G>A(p.Arg102Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,455,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

FBXO48
NM_001024680.3 missense, splice_region

Scores

Splicing: ADA: 0.0001685

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.26

Variant links:

Genes affected

FBXO48 (HGNC:33857): (F-box protein 48) Predicted to be involved in SCF-dependent proteasomal ubiquitin-dependent protein catabolic process. Predicted to be part of SCF ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

FBXO48 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.060441792).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO48	NM_001024680.3 link	c.305G>A	p.Arg102Lys	missense_variant, splice_region_variant	Exon 3 of 4	ENST00000377957.4	NP_001019851.1	Q5FWF7
FBXO48	XM_005264407.4 link	c.305G>A	p.Arg102Lys	missense_variant, splice_region_variant	Exon 3 of 4		XP_005264464.1	Q5FWF7
FBXO48	XM_017004437.3 link	c.305G>A	p.Arg102Lys	missense_variant, splice_region_variant	Exon 3 of 4		XP_016859926.1	Q5FWF7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO48	ENST00000377957.4 link	c.305G>A	p.Arg102Lys	missense_variant, splice_region_variant	Exon 3 of 4	1	NM_001024680.3	ENSP00000367193.2		Q5FWF7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

249214

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.0000265

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1455208

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

723544

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000812

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.305G>A (p.R102K) alteration is located in exon 3 (coding exon 1) of the FBXO48 gene. This alteration results from a G to A substitution at nucleotide position 305, causing the arginine (R) at amino acid position 102 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

Benign

0.12

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.014

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.71

M_CAP

Benign

0.0022

MetaRNN

Benign

0.060

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.090

PrimateAI

Benign

0.35

PROVEAN

Benign

0.55

REVEL

Benign

0.081

Sift

Benign

0.77

Sift4G

Benign

1.0

Polyphen

0.022

Vest4

0.045

MVP

0.18

MPC

0.17

ClinPred

0.077

GERP RS

3.9

Varity_R

0.087

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00017

dbscSNV1_RF

Benign

0.048

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