chr5-148425612-A-C

Position:

• chr5-148425612-A-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_205836.3(FBXO38):​c.1829A>C​(p.Gln610Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: FBXO38 NM_205836.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.061163723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO38	NM_205836.3	c.1829A>C	p.Gln610Pro	missense_variant	14/22	ENST00000340253.10	NP_995308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO38	ENST00000340253.10	c.1829A>C	p.Gln610Pro	missense_variant	14/22	5	NM_205836.3	ENSP00000342023.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 26, 2019

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with FBXO38-related disease. This variant is present in population databases (rs771845635, ExAC 0.001%). This sequence change replaces glutamine with proline at codon 610 of the FBXO38 protein (p.Gln610Pro). The glutamine residue is weakly conserved and there is a moderate physicochemical difference between glutamine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.017	.;T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.059
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D;D;D;.
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.061	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.12	N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.71	N;N;N;N
REVEL	Benign	0.045
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.38	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.20
MutPred		0.16		Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);
MVP		0.093
MPC		0.58
ClinPred		0.33	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.051
gMVP		0.24

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: rs771845635; hg19: chr5-147805175;