6-145804978-C-G

Position:

chr6-145804978-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_032145.5(FBXO30):c.1428G>C(p.Glu476Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,772 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 1 hom. )

Consequence

FBXO30
NM_032145.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.812

Variant links:

Genes affected

FBXO30 (HGNC:15600): (F-box protein 30) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class and it is upregulated in nasopharyngeal carcinoma. [provided by RefSeq, Jul 2008]

FBXO30 links:

EPM2A-DT (HGNC:):

EPM2A-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019410223).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO30	NM_032145.5 linkuse as main transcript	c.1428G>C	p.Glu476Asp	missense_variant	2/3	ENST00000237281.5	NP_115521.3
FBXO30	NM_001348092.2 linkuse as main transcript	c.1428G>C	p.Glu476Asp	missense_variant	2/3		NP_001335021.1	Q8TB52
FBXO30	XM_047419398.1 linkuse as main transcript	c.1536G>C	p.Glu512Asp	missense_variant	2/3		XP_047275354.1
EPM2A-DT	NR_038246.1 linkuse as main transcript	n.53-23383C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO30	ENST00000237281.5 linkuse as main transcript	c.1428G>C	p.Glu476Asp	missense_variant	2/3	1	NM_032145.5	ENSP00000237281.3		Q8TB52
EPM2A-DT	ENST00000629681.1 linkuse as main transcript	n.91-4800C>G		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000112

AC:

AN:

250912

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135606

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:

0.000882

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000424

AC:

AN:

1461598

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727084

show subpopulations

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:

0.000591

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.000173

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.1428G>C (p.E476D) alteration is located in exon 2 (coding exon 1) of the FBXO30 gene. This alteration results from a G to C substitution at nucleotide position 1428, causing the glutamic acid (E) at amino acid position 476 to be replaced by an aspartic acid (D). 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

0.17

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.47

CADD

Benign

7.9

DANN

Benign

0.28

DEOGEN2

Benign

0.028

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0052

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.30

PrimateAI

Uncertain

0.78

PROVEAN

Benign

1.8

REVEL

Benign

0.12

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0070

Vest4

0.17

MutPred

0.68

Loss of helix (P = 0.0444);

MVP

0.16

MPC

0.21

ClinPred

0.016

GERP RS

-0.85

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.47

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