rs148337492

chr5-148394787-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_205836.3(FBXO38):c.11G>A(p.Arg4Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000585 in 1,573,276 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: FBXO38 NM_205836.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1 O:1
• Conservation: PhyloP100: 8.22

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FBXO38
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXO38	NM_205836.3	c.11G>A	p.Arg4Gln	missense_variant	2/22	ENST00000340253.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXO38	ENST00000340253.10	c.11G>A	p.Arg4Gln	missense_variant	2/22	5	NM_205836.3	P3

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000856 AC: 19 AN: 221986 Hom.: 0 AF XY: 0.0000994 AC XY: 12 AN XY: 120782

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000584 AC: 83 AN: 1421216 Hom.: 0 Cov.: 30 AF XY: 0.0000580 AC XY: 41 AN XY: 706604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000262

Gnomad4 ASJ exome AF: 0.0000400

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000723

Gnomad4 OTH exome AF: 0.0000341

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74266

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000194 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neuronopathy, distal hereditary motor, type 2D Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 20, 2019	- -

Distal hereditary motor neuropathy type 2 Uncertain:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4 of the FBXO38 protein (p.Arg4Gln). This variant is present in population databases (rs148337492, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FBXO38-related conditions. ClinVar contains an entry for this variant (Variation ID: 541015). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBXO38 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;.
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.2	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.85
MVP		0.44
MPC		1.7
ClinPred		0.70	D
GERP RS		4.7
Varity_R		0.59
gMVP		0.60

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

Other links and lift over

dbSNP: rs148337492; hg19: chr5-147774350;