rs148580014

Variant names:

• chr5-148438372-T-G
• rs148580014
• NM_205836.3:c.2898T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_205836.3(FBXO38):​c.2898T>G​(p.Asn966Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,896 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBXO38 NM_205836.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.478
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15133035).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO38	NM_205836.3	MANE Select	c.2898T>G	p.Asn966Lys	missense	Exon 18 of 22	NP_995308.1	Q6PIJ6-1
	FBXO38	NM_030793.5		c.2673T>G	p.Asn891Lys	missense	Exon 18 of 22	NP_110420.3
	FBXO38	NM_001271723.2		c.2163T>G	p.Asn721Lys	missense	Exon 17 of 21	NP_001258652.1	Q6PIJ6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO38	ENST00000340253.10	TSL:5 MANE Select	c.2898T>G	p.Asn966Lys	missense	Exon 18 of 22	ENSP00000342023.6	Q6PIJ6-1
	FBXO38	ENST00000394370.7	TSL:1	c.2673T>G	p.Asn891Lys	missense	Exon 18 of 22	ENSP00000377895.3	Q6PIJ6-2
	FBXO38	ENST00000513826.1	TSL:1	c.2163T>G	p.Asn721Lys	missense	Exon 16 of 20	ENSP00000426410.1	Q6PIJ6-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461706 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111886

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000387 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Distal hereditary motor neuropathy type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.090
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.48
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.056
Sift	Benign	0.55	T
Sift4G	Benign	0.28	T
Polyphen		0.21	B
Vest4		0.50
MutPred		0.36		Loss of sheet (P = 0.0315)
MVP		0.11
MPC		0.90
ClinPred		0.66	D
GERP RS		3.5
Varity_R		0.30
gMVP		0.40
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs148580014; hg19: chr5-147817935;