Genetic Variant FBXO48:p.Glu117Lys (chr2-68464328-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001024680.3(FBXO48):c.349G>A(p.Glu117Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

FBXO48
NM_001024680.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.99

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14235985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO48	NM_001024680.3 link	c.349G>A	p.Glu117Lys	missense_variant	Exon 4 of 4	ENST00000377957.4	NP_001019851.1	Q5FWF7
FBXO48	XM_005264407.4 link	c.349G>A	p.Glu117Lys	missense_variant	Exon 4 of 4		XP_005264464.1	Q5FWF7
FBXO48	XM_017004437.3 link	c.349G>A	p.Glu117Lys	missense_variant	Exon 4 of 4		XP_016859926.1	Q5FWF7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO48	ENST00000377957.4 link	c.349G>A	p.Glu117Lys	missense_variant	Exon 4 of 4	1	NM_001024680.3	ENSP00000367193.2		Q5FWF7

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251350

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461564

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152016

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000258

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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.349G>A (p.E117K) alteration is located in exon 4 (coding exon 2) of the FBXO48 gene. This alteration results from a G to A substitution at nucleotide position 349, causing the glutamic acid (E) at amino acid position 117 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

0.23

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

Eigen

Benign

0.096

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0071

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.3

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.72

REVEL

Benign

0.14

Sift

Benign

0.18

Sift4G

Benign

0.35

Polyphen

0.98

Vest4

0.17

MVP

0.42

MPC

0.20

ClinPred

0.16

GERP RS

4.1

Varity_R

0.10

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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