rs3131561

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr15-50481558-A-C
• chr15-50481558-A-G

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP8	NM_005154.5	c.1296A>C	p.Gln432His	missense_variant	Exon 11 of 20	ENST00000307179.9	NP_005145.3
USP8	NM_001128610.3	c.1296A>C	p.Gln432His	missense_variant	Exon 11 of 20		NP_001122082.1
USP8	NM_001283049.2	c.1065A>C	p.Gln355His	missense_variant	Exon 9 of 17		NP_001269978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP8	ENST00000307179.9	c.1296A>C	p.Gln432His	missense_variant	Exon 11 of 20	1	NM_005154.5	ENSP00000302239.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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