5-148425557-T-C

Variant names:

• chr5-148425557-T-C
• rs10043775
• NM_205836.3:c.1774T>C

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.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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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
• Publications: 48 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 (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 VariationId is 1169150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.292 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.1774T>C	p.Ser592Pro	missense	Exon 14 of 22	NP_995308.1
	FBXO38	NM_030793.5		c.1774T>C	p.Ser592Pro	missense	Exon 14 of 22	NP_110420.3
	FBXO38	NM_001271723.2		c.1774T>C	p.Ser592Pro	missense	Exon 14 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.1774T>C	p.Ser592Pro	missense	Exon 14 of 22	ENSP00000342023.6
	FBXO38	ENST00000394370.7	TSL:1	c.1774T>C	p.Ser592Pro	missense	Exon 14 of 22	ENSP00000377895.3
	FBXO38	ENST00000513826.1	TSL:1	c.1774T>C	p.Ser592Pro	missense	Exon 13 of 20	ENSP00000426410.1

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

GnomAD2 exomes AF: 0.268 AC: 67370 AN: 251128 AF XY: 0.269

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 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

African (AFR) AF: 0.300 AC: 10030 AN: 33444

American (AMR) AF: 0.284 AC: 12676 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 5074 AN: 26128

East Asian (EAS) AF: 0.198 AC: 7871 AN: 39690

South Asian (SAS) AF: 0.294 AC: 25302 AN: 86206

European-Finnish (FIN) AF: 0.234 AC: 12516 AN: 53416

Middle Eastern (MID) AF: 0.270 AC: 1557 AN: 5768

European-Non Finnish (NFE) AF: 0.270 AC: 299945 AN: 1110834

Other (OTH) AF: 0.258 AC: 15580 AN: 60350

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

African (AFR) AF: 0.297 AC: 12282 AN: 41374

American (AMR) AF: 0.261 AC: 3993 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 702 AN: 3472

East Asian (EAS) AF: 0.242 AC: 1247 AN: 5154

South Asian (SAS) AF: 0.290 AC: 1394 AN: 4810

European-Finnish (FIN) AF: 0.228 AC: 2408 AN: 10556

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18352 AN: 67938

Other (OTH) AF: 0.254 AC: 535 AN: 2106

Alfa AF: 0.269 Hom.: 19907

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

ClinVar submissions as Germline

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
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	19
DANN	Benign	0.81
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.1	N
PhyloP100		3.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.096
Sift	Benign	1.0	T
Sift4G	Benign	0.89	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.14
ClinPred		0.0025	T
GERP RS		4.9
Varity_R		0.10
gMVP		0.096
Mutation Taster		=97/3	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: rs10043775; hg19: chr5-147805120; COSMIC: COSV57026526; COSMIC: COSV57026526;