rs3743044

Variant names:

• chr15-50481590-A-G
• rs3743044
• NM_005154.5:c.1328A>G
• USP8 p.Asp443Gly

Variant summary

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

The NM_005154.5(USP8):​c.1328A>G​(p.Asp443Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,614,032 control chromosomes in the GnomAD database, including 1,316 homozygotes. In-silico tool predicts 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. D443V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.030 (91 hom., cov: 33)
  • Exomes 𝑓: 0.033 (1225 hom.)
• Consequence: USP8 NM_005154.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.38
• Publications: 23 publications found

Genes affected

USP8 (HGNC:12631): (ubiquitin specific peptidase 8) This gene encodes a protein that belongs to the ubiquitin-specific processing protease family of proteins. The encoded protein is thought to regulate the morphology of the endosome by ubiquitination of proteins on this organelle and is involved in cargo sorting and membrane trafficking at the early endosome stage. This protein is required for the cell to enter the S phase of the cell cycle and also functions as a positive regulator in the Hedgehog signaling pathway in development. Pseudogenes of this gene are present on chromosomes 2 and 6. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

USP8 Gene-Disease associations (from GenCC):

• autosomal recessive spastic paraplegia type 59

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary spastic paraplegia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069358647).
• BP6: Variant 15-50481590-A-G is Benign according to our data. Variant chr15-50481590-A-G is described in ClinVar as Benign. ClinVar VariationId is 458312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0888 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005154.5. 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
	USP8	NM_005154.5	MANE Select	c.1328A>G	p.Asp443Gly	missense	Exon 11 of 20	NP_005145.3
	USP8	NM_001128610.3		c.1328A>G	p.Asp443Gly	missense	Exon 11 of 20	NP_001122082.1	P40818-1
	USP8	NM_001283049.2		c.1097A>G	p.Asp366Gly	missense	Exon 9 of 17	NP_001269978.1	P40818-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP8	ENST00000307179.9	TSL:1 MANE Select	c.1328A>G	p.Asp443Gly	missense	Exon 11 of 20	ENSP00000302239.4	P40818-1
	USP8	ENST00000396444.7	TSL:1	c.1328A>G	p.Asp443Gly	missense	Exon 11 of 20	ENSP00000379721.3	P40818-1
	USP8	ENST00000559329.5	TSL:1	n.1328A>G		non_coding_transcript_exon	Exon 12 of 12	ENSP00000454003.1	A0A075B720

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4487 AN: 152158 Hom.: 91 Cov.: 33

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.0959

Gnomad SAS AF: 0.0762

Gnomad FIN AF: 0.0351

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0290

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.0354 AC: 8883 AN: 251158 AF XY: 0.0364

Gnomad AFR exome AF: 0.0162

Gnomad AMR exome AF: 0.0247

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.0736

Gnomad FIN exome AF: 0.0348

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.0328 AC: 47938 AN: 1461756 Hom.: 1225 Cov.: 31 AF XY: 0.0337 AC XY: 24498 AN XY: 727162

African (AFR) AF: 0.0161 AC: 540 AN: 33468

American (AMR) AF: 0.0244 AC: 1091 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0186 AC: 486 AN: 26132

East Asian (EAS) AF: 0.131 AC: 5218 AN: 39682

South Asian (SAS) AF: 0.0636 AC: 5480 AN: 86226

European-Finnish (FIN) AF: 0.0330 AC: 1760 AN: 53410

Middle Eastern (MID) AF: 0.0168 AC: 97 AN: 5764

European-Non Finnish (NFE) AF: 0.0280 AC: 31190 AN: 1111966

Other (OTH) AF: 0.0344 AC: 2076 AN: 60392

GnomAD4 genome AF: 0.0295 AC: 4494 AN: 152276 Hom.: 91 Cov.: 33 AF XY: 0.0311 AC XY: 2315 AN XY: 74458

African (AFR) AF: 0.0191 AC: 793 AN: 41554

American (AMR) AF: 0.0234 AC: 357 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3470

East Asian (EAS) AF: 0.0958 AC: 496 AN: 5180

South Asian (SAS) AF: 0.0750 AC: 362 AN: 4828

European-Finnish (FIN) AF: 0.0351 AC: 373 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0290 AC: 1972 AN: 68022

Other (OTH) AF: 0.0260 AC: 55 AN: 2114

Alfa AF: 0.0301 Hom.: 434

Bravo AF: 0.0254

Asia WGS AF: 0.127 AC: 440 AN: 3478

EpiCase AF: 0.0274

EpiControl AF: 0.0294

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.4
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.033	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.27
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3743044;

hg19: chr15-50773787;

COSMIC: COSV56168864;