chr5-148399109-G-A

Position:

• chr5-148399109-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_205836.3(FBXO38):​c.239G>A​(p.Arg80Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,461,076 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: FBXO38 NM_205836.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.21

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 -4 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBXO38. . Gene score misZ 2.8126 (greater than the threshold 3.09). Trascript score misZ 3.83 (greater than threshold 3.09). GenCC has associacion of gene with distal hereditary motor neuropathy type 2, neuronopathy, distal hereditary motor, type 2D, distal hereditary motor neuropathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3276853).
• BS2: High AC in GnomAdExome4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO38	NM_205836.3	c.239G>A	p.Arg80Gln	missense_variant	3/22	ENST00000340253.10	NP_995308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO38	ENST00000340253.10	c.239G>A	p.Arg80Gln	missense_variant	3/22	5	NM_205836.3	ENSP00000342023	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250916 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135620

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461076 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 726836

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Distal hereditary motor neuropathy type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 24, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 80 of the FBXO38 protein (p.Arg80Gln). This variant is present in population databases (rs751167811, gnomAD 0.003%). 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: 473955). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 22, 2022

BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.057	.;T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D;D;.
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.0	N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.097	T;T;D;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.99	D;P;P;D
Vest4		0.41
MutPred		0.42		Loss of MoRF binding (P = 0.04);Loss of MoRF binding (P = 0.04);Loss of MoRF binding (P = 0.04);Loss of MoRF binding (P = 0.04);
MVP		0.32
MPC		1.7
ClinPred		0.89	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.57

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: rs751167811; hg19: chr5-147778672; COSMIC: COSV57030877; COSMIC: COSV57030877;