15-50490450-C-T

Variant names:

• chr15-50490450-C-T
• rs672601311
• NM_005154.5:c.2159C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005154.5(USP8):​c.2159C>T​(p.Pro720Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USP8 NM_005154.5 missense
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP8	NM_005154.5	c.2159C>T	p.Pro720Leu	missense_variant	Exon 14 of 20	ENST00000307179.9	NP_005145.3
USP8	NM_001128610.3	c.2159C>T	p.Pro720Leu	missense_variant	Exon 14 of 20		NP_001122082.1
USP8	NM_001283049.2	c.1841C>T	p.Pro614Leu	missense_variant	Exon 11 of 17		NP_001269978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP8	ENST00000307179.9	c.2159C>T	p.Pro720Leu	missense_variant	Exon 14 of 20	1	NM_005154.5	ENSP00000302239.4
USP8	ENST00000396444.7	c.2159C>T	p.Pro720Leu	missense_variant	Exon 14 of 20	1		ENSP00000379721.3
USP8	ENST00000425032.7	c.1841C>T	p.Pro614Leu	missense_variant	Exon 11 of 17	2		ENSP00000412682.3
USP8	ENST00000561206.1	n.*20C>T		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: 0.00 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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	.;D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.056	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.64
MutPred		0.17		Gain of MoRF binding (P = 0.046);Gain of MoRF binding (P = 0.046);.;
MVP		0.26
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs672601311; hg19: chr15-50782647; COSMIC: COSV56165591; COSMIC: COSV56165591;