rs200187682

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_205836.3(FBXO38):c.1394G>A(p.Arg465His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,598,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R465C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

FBXO38
NM_205836.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 7.77

Publications

2 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027974397).

BP6

Variant 5-148416057-G-A is Benign according to our data. Variant chr5-148416057-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 473948.

BS2

High AC in GnomAd4 at 16 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_205836.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXO38	NM_205836.3	MANE Select	c.1394G>A	p.Arg465His	missense	Exon 11 of 22	NP_995308.1	Q6PIJ6-1
FBXO38	NM_030793.5		c.1394G>A	p.Arg465His	missense	Exon 11 of 22	NP_110420.3
FBXO38	NM_001271723.2		c.1394G>A	p.Arg465His	missense	Exon 11 of 21	NP_001258652.1	Q6PIJ6-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXO38	ENST00000340253.10	TSL:5 MANE Select	c.1394G>A	p.Arg465His	missense	Exon 11 of 22	ENSP00000342023.6	Q6PIJ6-1
FBXO38	ENST00000394370.7	TSL:1	c.1394G>A	p.Arg465His	missense	Exon 11 of 22	ENSP00000377895.3	Q6PIJ6-2
FBXO38	ENST00000513826.1	TSL:1	c.1394G>A	p.Arg465His	missense	Exon 10 of 20	ENSP00000426410.1	Q6PIJ6-3

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151806

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000297

AC:

AN:

239182

AF XY:

0.000317

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00630

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000916

Gnomad OTH exome

AF:

0.000350

GnomAD4 exome

AF:

0.000145

AC:

210

AN:

1446474

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

106

AN XY:

718288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32704

American (AMR)

AF:

0.00

AC:

AN:

42718

Ashkenazi Jewish (ASJ)

AF:

0.00591

AC:

151

AN:

25534

East Asian (EAS)

AF:

0.00

AC:

AN:

39212

South Asian (SAS)

AF:

0.00

AC:

AN:

83944

European-Finnish (FIN)

AF:

0.0000377

AC:

AN:

53112

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.0000326

AC:

AN:

1103868

Other (OTH)

AF:

0.000335

AC:

AN:

59700

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000105

AC:

AN:

151806

Hom.:

Cov.:

AF XY:

0.0000944

AC XY:

AN XY:

74114

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41334

American (AMR)

AF:

0.00

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67962

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.000456

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000296

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Distal hereditary motor neuropathy type 2 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.020

MetaRNN

Benign

0.028

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.90

PhyloP100

7.8

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.32

Sift

Uncertain

0.013

Sift4G

Uncertain

0.037

Polyphen

1.0

Vest4

0.72

MVP

0.41

MPC

1.8

ClinPred

0.16

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.63

Mutation Taster

=72/28

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

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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

Computational scores

Splicing

Publications

Other links and lift over