Genetic Variant FBXO38:p.Leu66Leu (chr5-148399068-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_205836.3(FBXO38):c.198A>G(p.Leu66Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,613,538 control chromosomes in the GnomAD database, including 530 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 73 hom., cov: 32)

Exomes 𝑓: 0.013 ( 457 hom. )

Consequence

FBXO38
NM_205836.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.09

Variant links:

Genes affected

FBXO38 (HGNC:28844): (F-box protein 38) This gene encodes a large protein that contains an F-box domain and may participate in protein ubiquitination. The encoded protein is a transcriptional co-activator of Krueppel-like factor 7 (Klf7). A heterozygous mutation in this gene was found in individuals with autosomal dominant distal hereditary motor neuronopathy type IID. There is a pseudogene for this gene on chromosome 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

FBXO38 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 5-148399068-A-G is Benign according to our data. Variant chr5-148399068-A-G is described in ClinVar as [Benign]. Clinvar id is 473951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148399068-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.1 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO38	NM_205836.3 link	c.198A>G	p.Leu66Leu	synonymous_variant	Exon 3 of 22	ENST00000340253.10	NP_995308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO38	ENST00000340253.10 link	c.198A>G	p.Leu66Leu	synonymous_variant	Exon 3 of 22	5	NM_205836.3	ENSP00000342023.6		Q6PIJ6-1

Frequencies

GnomAD3 genomes

AF:

0.0175

AC:

2660

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00731

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0673

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.0688

Gnomad SAS

AF:

0.0522

Gnomad FIN

AF:

0.00998

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00720

Gnomad OTH

AF:

0.0215

GnomAD3 exomes

AF:

0.0275

AC:

6916

AN:

251186

Hom.:

239

AF XY:

0.0268

AC XY:

3632

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.00801

Gnomad AMR exome

AF:

0.0759

Gnomad ASJ exome

AF:

0.0208

Gnomad EAS exome

AF:

0.0646

Gnomad SAS exome

AF:

0.0519

Gnomad FIN exome

AF:

0.0126

Gnomad NFE exome

AF:

0.00674

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0131

AC:

19212

AN:

1461286

Hom.:

457

Cov.:

AF XY:

0.0139

AC XY:

10126

AN XY:

726940

show subpopulations

Gnomad4 AFR exome

AF:

0.00766

Gnomad4 AMR exome

AF:

0.0719

Gnomad4 ASJ exome

AF:

0.0214

Gnomad4 EAS exome

AF:

0.0641

Gnomad4 SAS exome

AF:

0.0489

Gnomad4 FIN exome

AF:

0.0127

Gnomad4 NFE exome

AF:

0.00589

Gnomad4 OTH exome

AF:

0.0183

GnomAD4 genome

AF:

0.0175

AC:

2657

AN:

152252

Hom.:

Cov.:

AF XY:

0.0200

AC XY:

1490

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00734

Gnomad4 AMR

AF:

0.0671

Gnomad4 ASJ

AF:

0.0210

Gnomad4 EAS

AF:

0.0685

Gnomad4 SAS

AF:

0.0516

Gnomad4 FIN

AF:

0.00998

Gnomad4 NFE

AF:

0.00721

Gnomad4 OTH

AF:

0.0218

Alfa

AF:

0.00889

Hom.:

Bravo

AF:

0.0199

Asia WGS

AF:

0.0850

AC:

293

AN:

3478

EpiCase

AF:

0.00949

EpiControl

AF:

0.00848

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Distal hereditary motor neuropathy type 2

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Apr 17, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.1

DANN

Benign

0.51

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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