chr15-50477323-G-A

Position:

• chr15-50477323-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005154.5(USP8):​c.1042G>A​(p.Ala348Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 1,613,798 control chromosomes in the GnomAD database, including 1,332 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (78 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1254 hom.)
• Consequence: USP8 NM_005154.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.114

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001880914).
• BP6: Variant 15-50477323-G-A is Benign according to our data. Variant chr15-50477323-G-A is described in ClinVar as [Benign]. Clinvar id is 458310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.026 (3952/152178) while in subpopulation NFE AF= 0.0416 (2827/68000). AF 95% confidence interval is 0.0403. There are 78 homozygotes in gnomad4. There are 1787 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3952 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP8	NM_005154.5	c.1042G>A	p.Ala348Thr	missense_variant	10/20	ENST00000307179.9	NP_005145.3
USP8	NM_001128610.3	c.1042G>A	p.Ala348Thr	missense_variant	10/20		NP_001122082.1
USP8	NM_001283049.2	c.811G>A	p.Ala271Thr	missense_variant	8/17		NP_001269978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP8	ENST00000307179.9	c.1042G>A	p.Ala348Thr	missense_variant	10/20	1	NM_005154.5	ENSP00000302239	P1

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3954 AN: 152060 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00833

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0273

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0259 AC: 6498 AN: 250846 Hom.: 111 AF XY: 0.0266 AC XY: 3616 AN XY: 135768

Gnomad AFR exome AF: 0.00650

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.0310

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00713

Gnomad FIN exome AF: 0.0166

Gnomad NFE exome AF: 0.0414

Gnomad OTH exome AF: 0.0319

GnomAD4 exome AF: 0.0384 AC: 56111 AN: 1461620 Hom.: 1254 Cov.: 31 AF XY: 0.0375 AC XY: 27287 AN XY: 727122

Gnomad4 AFR exome AF: 0.00681

Gnomad4 AMR exome AF: 0.0194

Gnomad4 ASJ exome AF: 0.0306

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00707

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.0454

Gnomad4 OTH exome AF: 0.0349

GnomAD4 genome AF: 0.0260 AC: 3952 AN: 152178 Hom.: 78 Cov.: 32 AF XY: 0.0240 AC XY: 1787 AN XY: 74398

Gnomad4 AFR AF: 0.00831

Gnomad4 AMR AF: 0.0272

Gnomad4 ASJ AF: 0.0343

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.0133

Gnomad4 NFE AF: 0.0416

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0389 Hom.: 104

Bravo AF: 0.0270

TwinsUK AF: 0.0372 AC: 138

ALSPAC AF: 0.0410 AC: 158

ESP6500AA AF: 0.0105 AC: 46

ESP6500EA AF: 0.0434 AC: 373

ExAC AF: 0.0255 AC: 3090

Asia WGS AF: 0.00462 AC: 17 AN: 3476

EpiCase AF: 0.0426

EpiControl AF: 0.0424

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.54
DANN	Benign	0.37
DEOGEN2	Benign	0.025	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.61	.;T;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.26	N;N;N
REVEL	Benign	0.050
Sift	Benign	0.52	T;T;T
Sift4G	Benign	0.59	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.020
ClinPred		0.0012	T
GERP RS		-9.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.017
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61733869; hg19: chr15-50769520;