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

Variant summary

Our verdict is Benign. The variant received -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

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

neuronopathy, distal hereditary motor, type 2D
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
distal hereditary motor neuropathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
distal hereditary motor neuropathy type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FBXO38 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 473951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

GnomAD2 exomes

AF:

0.0275

AC:

6916

AN:

251186

AF XY:

0.0268

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 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

African (AFR)

AF:

0.00766

AC:

256

AN:

33440

American (AMR)

AF:

0.0719

AC:

3210

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.0214

AC:

559

AN:

26108

East Asian (EAS)

AF:

0.0641

AC:

2542

AN:

39684

South Asian (SAS)

AF:

0.0489

AC:

4216

AN:

86244

European-Finnish (FIN)

AF:

0.0127

AC:

677

AN:

53416

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00589

AC:

6550

AN:

1111640

Other (OTH)

AF:

0.0183

AC:

1105

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

919

1837

2756

3674

4593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

376

752

1128

1504

1880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0175

AC:

2657

AN:

152252

Hom.:

Cov.:

AF XY:

0.0200

AC XY:

1490

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00734

AC:

305

AN:

41566

American (AMR)

AF:

0.0671

AC:

1026

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

AN:

3472

East Asian (EAS)

AF:

0.0685

AC:

354

AN:

5166

South Asian (SAS)

AF:

0.0516

AC:

249

AN:

4826

European-Finnish (FIN)

AF:

0.00998

AC:

106

AN:

10618

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00721

AC:

490

AN:

68004

Other (OTH)

AF:

0.0218

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

129

257

386

514

643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00976

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

(source)

DANN

Benign

0.51

PhyloP100

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over