chr5-148409235-A-G

Variant names:

• chr5-148409235-A-G
• rs10077690
• NM_205836.3:c.962+18A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_205836.3(FBXO38):​c.962+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,472,562 control chromosomes in the GnomAD database, including 40,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3332 hom., cov: 32)
  • Exomes 𝑓: 0.24 (36689 hom.)
• Consequence: FBXO38 NM_205836.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.13
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-148409235-A-G is Benign according to our data. Variant chr5-148409235-A-G is described in ClinVar as Benign. ClinVar VariationId is 1235574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

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.962+18A>G		intron	N/A	NP_995308.1	Q6PIJ6-1
	FBXO38	NM_030793.5		c.962+18A>G		intron	N/A	NP_110420.3
	FBXO38	NM_001271723.2		c.962+18A>G		intron	N/A	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.962+18A>G		intron	N/A	ENSP00000342023.6	Q6PIJ6-1
	FBXO38	ENST00000394370.7	TSL:1	c.962+18A>G		intron	N/A	ENSP00000377895.3	Q6PIJ6-2
	FBXO38	ENST00000513826.1	TSL:1	c.962+18A>G		intron	N/A	ENSP00000426410.1	Q6PIJ6-3

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31262 AN: 151896 Hom.: 3327 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.202

GnomAD2 exomes AF: 0.230 AC: 57852 AN: 251140 AF XY: 0.232

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.249

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.235

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.235 AC: 310796 AN: 1320548 Hom.: 36689 Cov.: 20 AF XY: 0.235 AC XY: 156233 AN XY: 664606

African (AFR) AF: 0.139 AC: 4235 AN: 30476

American (AMR) AF: 0.264 AC: 11759 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4394 AN: 25232

East Asian (EAS) AF: 0.198 AC: 7728 AN: 38946

South Asian (SAS) AF: 0.233 AC: 19451 AN: 83370

European-Finnish (FIN) AF: 0.217 AC: 11542 AN: 53266

Middle Eastern (MID) AF: 0.228 AC: 1256 AN: 5498

European-Non Finnish (NFE) AF: 0.242 AC: 237951 AN: 983484

Other (OTH) AF: 0.224 AC: 12480 AN: 55778

GnomAD4 genome AF: 0.206 AC: 31263 AN: 152014 Hom.: 3332 Cov.: 32 AF XY: 0.204 AC XY: 15169 AN XY: 74304

African (AFR) AF: 0.141 AC: 5844 AN: 41460

American (AMR) AF: 0.229 AC: 3494 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 629 AN: 3470

East Asian (EAS) AF: 0.241 AC: 1249 AN: 5172

South Asian (SAS) AF: 0.234 AC: 1128 AN: 4820

European-Finnish (FIN) AF: 0.212 AC: 2232 AN: 10540

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16093 AN: 67954

Other (OTH) AF: 0.202 AC: 426 AN: 2112

Alfa AF: 0.222 Hom.: 5056

Bravo AF: 0.202

Asia WGS AF: 0.228 AC: 792 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Distal hereditary motor neuropathy type 2 (1)
-	-	1	Neuronopathy, distal hereditary motor, type 2D (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.027
DANN	Benign	0.53
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs10077690; hg19: chr5-147788798; COSMIC: COSV57027953; COSMIC: COSV57027953;