rs772345898

chr5-148424084-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_205836.3(FBXO38):c.1705A>G(p.Ile569Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: FBXO38 NM_205836.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

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 Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FBXO38
• BP4: Computational evidence support a benign effect (MetaRNN=0.01842609).
• BS2: High AC in GnomAdExome at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXO38	NM_205836.3	c.1705A>G	p.Ile569Val	missense_variant	13/22	ENST00000340253.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXO38	ENST00000340253.10	c.1705A>G	p.Ile569Val	missense_variant	13/22	5	NM_205836.3	P3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152194 Hom.: 0 Cov.: 33

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000359 AC: 9 AN: 250748 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135542

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461370 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727008

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Distal hereditary motor neuropathy type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 01, 2023

This variant has not been reported in the literature in individuals affected with FBXO38-related conditions. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 569 of the FBXO38 protein (p.Ile569Val). This variant is present in population databases (rs772345898, gnomAD 0.03%). ClinVar contains an entry for this variant (Variation ID: 575466). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	4.8
Dann	Benign	0.53
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.73	T;T;T;.
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.018	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.0	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.35	N;N;N;N
REVEL	Benign	0.020
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.087
MutPred		0.24		Loss of catalytic residue at P571 (P = 0.0494);Loss of catalytic residue at P571 (P = 0.0494);Loss of catalytic residue at P571 (P = 0.0494);Loss of catalytic residue at P571 (P = 0.0494);
MVP		0.043
MPC		0.091
ClinPred		0.0067	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.013
gMVP		0.046

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: rs772345898; hg19: chr5-147803647;