5-148409186-C-T

Variant names:

• chr5-148409186-C-T
• rs142117467
• NM_205836.3:c.931C>T

Variant summary

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

The NM_205836.3(FBXO38):​c.931C>T​(p.Leu311Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,458 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L311I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FBXO38 NM_205836.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.66
• Publications: 6 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO38	NM_205836.3	MANE Select	c.931C>T	p.Leu311Phe	missense	Exon 8 of 22	NP_995308.1
	FBXO38	NM_030793.5		c.931C>T	p.Leu311Phe	missense	Exon 8 of 22	NP_110420.3
	FBXO38	NM_001271723.2		c.931C>T	p.Leu311Phe	missense	Exon 8 of 21	NP_001258652.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO38	ENST00000340253.10	TSL:5 MANE Select	c.931C>T	p.Leu311Phe	missense	Exon 8 of 22	ENSP00000342023.6
	FBXO38	ENST00000394370.7	TSL:1	c.931C>T	p.Leu311Phe	missense	Exon 8 of 22	ENSP00000377895.3
	FBXO38	ENST00000513826.1	TSL:1	c.931C>T	p.Leu311Phe	missense	Exon 7 of 20	ENSP00000426410.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251368 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459458 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 726220

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109926

Other (OTH) AF: 0.00 AC: 0 AN: 60304

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.48		Loss of helix (P = 0.0167)
MVP		0.45
MPC		1.7
ClinPred		0.91	D
GERP RS		5.4
Varity_R		0.50
gMVP		0.70
Mutation Taster		=45/55	disease causing

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: rs142117467; hg19: chr5-147788749;