5-148433338-T-G

Variant names:

• chr5-148433338-T-G
• rs6861078
• NM_205836.3:c.2654-86T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_205836.3(FBXO38):​c.2654-86T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 855,618 control chromosomes in the GnomAD database, including 54,990 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.42 (15845 hom., cov: 32)
  • Exomes 𝑓: 0.32 (39145 hom.)
• Consequence: FBXO38 NM_205836.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.222
• Publications: 11 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-148433338-T-G is Benign according to our data. Variant chr5-148433338-T-G is described in ClinVar as Benign. ClinVar VariationId is 1223057.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.681 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO38	NM_205836.3	MANE Select	c.2654-86T>G		intron	N/A	NP_995308.1
	FBXO38	NM_030793.5		c.2429-86T>G		intron	N/A	NP_110420.3
	FBXO38	NM_001271723.2		c.1919-86T>G		intron	N/A	NP_001258652.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO38	ENST00000340253.10	TSL:5 MANE Select	c.2654-86T>G		intron	N/A	ENSP00000342023.6
	FBXO38	ENST00000394370.7	TSL:1	c.2429-86T>G		intron	N/A	ENSP00000377895.3
	FBXO38	ENST00000513826.1	TSL:1	c.1919-86T>G		intron	N/A	ENSP00000426410.1

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63743 AN: 151940 Hom.: 15795 Cov.: 32

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.384

GnomAD4 exome AF: 0.318 AC: 223608 AN: 703560 Hom.: 39145 Cov.: 9 AF XY: 0.319 AC XY: 117858 AN XY: 369768

African (AFR) AF: 0.679 AC: 11640 AN: 17152

American (AMR) AF: 0.406 AC: 12014 AN: 29592

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 4354 AN: 16938

East Asian (EAS) AF: 0.572 AC: 20291 AN: 35448

South Asian (SAS) AF: 0.386 AC: 22512 AN: 58290

European-Finnish (FIN) AF: 0.297 AC: 14742 AN: 49654

Middle Eastern (MID) AF: 0.321 AC: 1315 AN: 4094

European-Non Finnish (NFE) AF: 0.274 AC: 125433 AN: 457922

Other (OTH) AF: 0.328 AC: 11307 AN: 34470

GnomAD4 genome AF: 0.420 AC: 63849 AN: 152058 Hom.: 15845 Cov.: 32 AF XY: 0.419 AC XY: 31137 AN XY: 74336

African (AFR) AF: 0.688 AC: 28507 AN: 41454

American (AMR) AF: 0.396 AC: 6049 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 927 AN: 3470

East Asian (EAS) AF: 0.581 AC: 2993 AN: 5154

South Asian (SAS) AF: 0.393 AC: 1889 AN: 4810

European-Finnish (FIN) AF: 0.290 AC: 3068 AN: 10578

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19387 AN: 67986

Other (OTH) AF: 0.390 AC: 824 AN: 2112

Alfa AF: 0.368 Hom.: 2565

Bravo AF: 0.436

Asia WGS AF: 0.516 AC: 1794 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 08, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.89
DANN	Benign	0.77
PhyloP100		-0.22
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: rs6861078; hg19: chr5-147812901; COSMIC: COSV57032618; COSMIC: COSV57032618;