rs672601307

Positions:

• chr15-50490443-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_005154.5(USP8):​c.2152T>C​(p.Ser718Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USP8 NM_005154.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 5.95

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 5 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity UBP8_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-50490443-T-C is Pathogenic according to our data. Variant chr15-50490443-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 161992.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.2152T>C	p.Ser718Pro	missense_variant	14/20	ENST00000307179.9	NP_005145.3
USP8	NM_001128610.3	c.2152T>C	p.Ser718Pro	missense_variant	14/20		NP_001122082.1
USP8	NM_001283049.2	c.1834T>C	p.Ser612Pro	missense_variant	11/17		NP_001269978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP8	ENST00000307179.9	c.2152T>C	p.Ser718Pro	missense_variant	14/20	1	NM_005154.5	ENSP00000302239	P1
USP8	ENST00000396444.7	c.2152T>C	p.Ser718Pro	missense_variant	14/20	1		ENSP00000379721	P1
USP8	ENST00000425032.7	c.1834T>C	p.Ser612Pro	missense_variant	11/17	2		ENSP00000412682
USP8	ENST00000561206.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 8.99e-7

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	0.99
BayesDel_addAF	Benign	-0.0032	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T;T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.65
MutPred		0.19		Loss of phosphorylation at S718 (P = 0.0017);Loss of phosphorylation at S718 (P = 0.0017);.;
MVP		0.27
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.76

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: rs672601307; hg19: chr15-50782640; COSMIC: COSV56162050; COSMIC: COSV56162050;