rs10043775

chr5-148425557-T-Cchr5-148425557-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_205836.3(FBXO38):c.1774T>C(p.Ser592Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,612,442 control chromosomes in the GnomAD database, including 58,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S592A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.27 (5608 hom., cov: 32)
  • Exomes 𝑓: 0.27 (52985 hom.)
• Consequence: FBXO38 NM_205836.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.44

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FBXO38
• BP4: Computational evidence support a benign effect (MetaRNN=0.0025879145).
• BP6: Variant 5-148425557-T-C is Benign according to our data. Variant chr5-148425557-T-C is described in ClinVar as [Benign]. Clinvar id is 1169150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148425557-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXO38	NM_205836.3	c.1774T>C	p.Ser592Pro	missense_variant	14/22	ENST00000340253.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXO38	ENST00000340253.10	c.1774T>C	p.Ser592Pro	missense_variant	14/22	5	NM_205836.3	P3

Frequencies

GnomAD3 genomes AF: 0.270 AC: 41055 AN: 151776 Hom.: 5597 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.255

GnomAD3 exomes AF: 0.268 AC: 67370 AN: 251128 Hom.: 9182 AF XY: 0.269 AC XY: 36539 AN XY: 135710

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.250

Gnomad SAS exome AF: 0.295

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.252

GnomAD4 exome AF: 0.267 AC: 390551 AN: 1460546 Hom.: 52985 Cov.: 32 AF XY: 0.268 AC XY: 194653 AN XY: 726636

Gnomad4 AFR exome AF: 0.300

Gnomad4 AMR exome AF: 0.284

Gnomad4 ASJ exome AF: 0.194

Gnomad4 EAS exome AF: 0.198

Gnomad4 SAS exome AF: 0.294

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.270

Gnomad4 OTH exome AF: 0.258

GnomAD4 genome AF: 0.271 AC: 41097 AN: 151896 Hom.: 5608 Cov.: 32 AF XY: 0.267 AC XY: 19845 AN XY: 74252

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.261

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.242

Gnomad4 SAS AF: 0.290

Gnomad4 FIN AF: 0.228

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.254

Alfa AF: 0.267 Hom.: 10244

Bravo AF: 0.272

TwinsUK AF: 0.274 AC: 1015

ALSPAC AF: 0.267 AC: 1029

ESP6500AA AF: 0.291 AC: 1284

ESP6500EA AF: 0.264 AC: 2267

ExAC AF: 0.269 AC: 32647

Asia WGS AF: 0.259 AC: 901 AN: 3478

EpiCase AF: 0.259

EpiControl AF: 0.268

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Distal hereditary motor neuropathy type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Neuronopathy, distal hereditary motor, type 2D Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	19
Dann	Benign	0.81
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.18	T;T;T;.
MetaRNN	Benign	0.0026	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.1	N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	2.1	N;N;N;N
REVEL	Benign	0.096
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.89	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.10
MPC		0.14
ClinPred		0.0025	T
GERP RS		4.9
Varity_R		0.10
gMVP		0.096

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: rs10043775; hg19: chr5-147805120; COSMIC: COSV57026526; COSMIC: COSV57026526;