NM_005154.5:c.1296A>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_005154.5(USP8):​c.1296A>G​(p.Gln432Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,612,928 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0078 (24 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (19 hom.)
• Consequence: USP8 NM_005154.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-50481558-A-G is Benign according to our data. Variant chr15-50481558-A-G is described in ClinVar as Benign. ClinVar VariationId is 528045.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.559 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0078 (1189/152366) while in subpopulation AFR AF = 0.0275 (1145/41580). AF 95% confidence interval is 0.0262. There are 24 homozygotes in GnomAd4. There are 559 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR,AD gene

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.1296A>G	p.Gln432Gln	synonymous	Exon 11 of 20	NP_005145.3
	USP8	NM_001128610.3		c.1296A>G	p.Gln432Gln	synonymous	Exon 11 of 20	NP_001122082.1
	USP8	NM_001283049.2		c.1065A>G	p.Gln355Gln	synonymous	Exon 9 of 17	NP_001269978.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP8	ENST00000307179.9	TSL:1 MANE Select	c.1296A>G	p.Gln432Gln	synonymous	Exon 11 of 20	ENSP00000302239.4
	USP8	ENST00000396444.7	TSL:1	c.1296A>G	p.Gln432Gln	synonymous	Exon 11 of 20	ENSP00000379721.3
	USP8	ENST00000559329.5	TSL:1	n.1296A>G		non_coding_transcript_exon	Exon 12 of 12	ENSP00000454003.1

Frequencies

GnomAD3 genomes AF: 0.00778 AC: 1185 AN: 152248 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.000857 AC: 1251 AN: 1460562 Hom.: 19 Cov.: 31 AF XY: 0.000723 AC XY: 525 AN XY: 726480

African (AFR) AF: 0.0313 AC: 1046 AN: 33410

American (AMR) AF: 0.000855 AC: 38 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111694

Other (OTH) AF: 0.00191 AC: 115 AN: 60352

GnomAD4 genome AF: 0.00780 AC: 1189 AN: 152366 Hom.: 24 Cov.: 32 AF XY: 0.00750 AC XY: 559 AN XY: 74516

African (AFR) AF: 0.0275 AC: 1145 AN: 41580

American (AMR) AF: 0.00170 AC: 26 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68038

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00347 Hom.: 6

Bravo AF: 0.00918

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
PhyloP100		-0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3131561; hg19: chr15-50773755;