15-50449489-C-A

Variant names:

• chr15-50449489-C-A
• rs373460543
• NM_005154.5:c.335+4C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005154.5(USP8):​c.335+4C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,375,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: USP8 NM_005154.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003024
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.383
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).

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.335+4C>A		splice_region intron	N/A	NP_005145.3
	USP8	NM_001128610.3		c.335+4C>A		splice_region intron	N/A	NP_001122082.1	P40818-1
	USP8	NM_001283049.2		c.105-9511C>A		intron	N/A	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.335+4C>A		splice_region intron	N/A	ENSP00000302239.4	P40818-1
	USP8	ENST00000396444.7	TSL:1	c.335+4C>A		splice_region intron	N/A	ENSP00000379721.3	P40818-1
	USP8	ENST00000559329.5	TSL:1	n.335+4C>A		splice_region intron	N/A	ENSP00000454003.1	A0A075B720

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1375106 Hom.: 0 Cov.: 23 AF XY: 0.00000146 AC XY: 1 AN XY: 684388

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30192

American (AMR) AF: 0.00 AC: 0 AN: 34384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23798

East Asian (EAS) AF: 0.00 AC: 0 AN: 38050

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5248

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062148

Other (OTH) AF: 0.00 AC: 0 AN: 56682

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.68
PhyloP100		-0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.012
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

Other links and lift over

dbSNP: rs373460543; hg19: chr15-50741686;