5-148427440-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_205836.3(FBXO38):c.2146A>G(p.Ser716Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000565 in 1,614,202 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (3 hom.)
• Consequence: FBXO38 NM_205836.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.58

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FBXO38
• BP4: Computational evidence support a benign effect (MetaRNN=0.005463332).
• BP6: Variant 5-148427440-A-G is Benign according to our data. Variant chr5-148427440-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 473952.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAd at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXO38	NM_205836.3	c.2146A>G	p.Ser716Gly	missense_variant	15/22	ENST00000340253.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXO38	ENST00000340253.10	c.2146A>G	p.Ser716Gly	missense_variant	15/22	5	NM_205836.3	P3
FBXO38	ENST00000394370.7	c.2146A>G	p.Ser716Gly	missense_variant	15/22	1		A1
FBXO38	ENST00000513826.1	c.1918+1739A>G		intron_variant		1		A1
FBXO38	ENST00000296701.10	c.1918+1739A>G		intron_variant		2		A1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000718 AC: 180 AN: 250750 Hom.: 1 AF XY: 0.000871 AC XY: 118 AN XY: 135540

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00418

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000857

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000570 AC: 833 AN: 1461872 Hom.: 3 Cov.: 32 AF XY: 0.000591 AC XY: 430 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00302

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000540

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152330 Hom.: 1 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74494

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000772 Hom.: 0

Bravo AF: 0.000574

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000725 AC: 88

EpiCase AF: 0.000709

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Distal hereditary motor neuropathy type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

FBXO38-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.012	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	0.023
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	0.91	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.12	N;N
REVEL	Benign	0.038
Sift	Benign	0.28	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.0	B;B
Vest4		0.31
MVP		0.15
MPC		0.50
ClinPred		0.013	T
GERP RS		4.7
Varity_R		0.059
gMVP		0.14

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: rs150893158; hg19: chr5-147807003; COSMIC: COSV57025839; COSMIC: COSV57025839;