5-148409186-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4BP6_Very_StrongBS2

The ENST00000340253.10(FBXO38):c.931C>A(p.Leu311Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000886 in 1,611,686 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L311L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00093 ( 2 hom. )

Consequence

FBXO38
ENST00000340253.10 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts P:1B:5

Conservation

PhyloP100: 3.66

Publications

6 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26680976).

BP6

Variant 5-148409186-C-A is Benign according to our data. Variant chr5-148409186-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 541003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 65 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000340253.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FBXO38	NM_205836.3	MANE Select	c.931C>A	p.Leu311Ile	missense	Exon 8 of 22	NP_995308.1
FBXO38	NM_030793.5		c.931C>A	p.Leu311Ile	missense	Exon 8 of 22	NP_110420.3
FBXO38	NM_001271723.2		c.931C>A	p.Leu311Ile	missense	Exon 8 of 21	NP_001258652.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FBXO38	ENST00000340253.10	TSL:5 MANE Select	c.931C>A	p.Leu311Ile	missense	Exon 8 of 22	ENSP00000342023.6
FBXO38	ENST00000394370.7	TSL:1	c.931C>A	p.Leu311Ile	missense	Exon 8 of 22	ENSP00000377895.3
FBXO38	ENST00000513826.1	TSL:1	c.931C>A	p.Leu311Ile	missense	Exon 7 of 20	ENSP00000426410.1

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000378

AC:

AN:

251368

AF XY:

0.000405

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000801

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000934

AC:

1363

AN:

1459432

Hom.:

Cov.:

AF XY:

0.000868

AC XY:

630

AN XY:

726212

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33408

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.000151

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00116

AC:

1289

AN:

1109900

Other (OTH)

AF:

0.00103

AC:

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

112

169

225

281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.000427

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41550

American (AMR)

AF:

0.000196

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000667

Hom.:

Bravo

AF:

0.000495

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000395

AC:

EpiCase

AF:

0.00109

EpiControl

AF:

0.000948

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease (1)

Distal hereditary motor neuropathy type 2 (1)

FBXO38-related disorder (1)

Neuronopathy, distal hereditary motor, type 2D (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.016

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.55

PhyloP100

3.7

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.1

REVEL

Benign

0.19

Sift

Benign

0.091

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.78

MVP

0.33

MPC

1.7

ClinPred

0.12

GERP RS

5.4

Varity_R

0.24

gMVP

0.45

Mutation Taster

=79/21

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over