rs672601311

Positions:

• chr15-50490450-C-G
• chr15-50490450-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_005154.5(USP8):​c.2159C>G​(p.Pro720Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: USP8 NM_005154.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 5.82

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-50490450-C-G is Pathogenic according to our data. Variant chr15-50490450-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 161995.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP8	NM_005154.5	c.2159C>G	p.Pro720Arg	missense_variant	14/20	ENST00000307179.9	NP_005145.3
USP8	NM_001128610.3	c.2159C>G	p.Pro720Arg	missense_variant	14/20		NP_001122082.1
USP8	NM_001283049.2	c.1841C>G	p.Pro614Arg	missense_variant	11/17		NP_001269978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP8	ENST00000307179.9	c.2159C>G	p.Pro720Arg	missense_variant	14/20	1	NM_005154.5	ENSP00000302239	P1
USP8	ENST00000396444.7	c.2159C>G	p.Pro720Arg	missense_variant	14/20	1		ENSP00000379721	P1
USP8	ENST00000425032.7	c.1841C>G	p.Pro614Arg	missense_variant	11/17	2		ENSP00000412682
USP8	ENST00000561206.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461890 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Pituitary dependent hypercortisolism Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 26, 2017	- -
Pathogenic, no assertion criteria provided	research	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 18, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.023	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.80
MutPred		0.20		Gain of MoRF binding (P = 0.0039);Gain of MoRF binding (P = 0.0039);.;
MVP		0.24
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.72

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: rs672601311; hg19: chr15-50782647; COSMIC: COSV56162692; COSMIC: COSV56162692;