chr15-50481558-A-C

Variant names:

• chr15-50481558-A-C
• rs3131561
• NM_005154.5:c.1296A>C

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.1296A>C​(p.Gln432His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q432Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP8 NM_005154.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.559
• Publications: 15 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 (MetaRNN=0.05614376).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP8	NM_005154.5	MANE Select	c.1296A>C	p.Gln432His	missense	Exon 11 of 20	NP_005145.3
	USP8	NM_001128610.3		c.1296A>C	p.Gln432His	missense	Exon 11 of 20	NP_001122082.1
	USP8	NM_001283049.2		c.1065A>C	p.Gln355His	missense	Exon 9 of 17	NP_001269978.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP8	ENST00000307179.9	TSL:1 MANE Select	c.1296A>C	p.Gln432His	missense	Exon 11 of 20	ENSP00000302239.4
	USP8	ENST00000396444.7	TSL:1	c.1296A>C	p.Gln432His	missense	Exon 11 of 20	ENSP00000379721.3
	USP8	ENST00000559329.5	TSL:1	n.1296A>C		non_coding_transcript_exon	Exon 12 of 12	ENSP00000454003.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.7
DEOGEN2	Benign	0.065	T
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.056	T
PhyloP100		-0.56
PROVEAN	Benign	-1.3	N
Sift	Benign	0.14	T
Sift4G	Benign	0.17	T
Vest4		0.060
gMVP		0.15

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

Other links and lift over

dbSNP: rs3131561; hg19: chr15-50773755;