rs1555462347

Variant names:

• chr16-8901027-GCT-G
• rs1555462347
• NM_003470.3:c.2169_2170delAG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003470.3(USP7):​c.2169_2170delAG​(p.Arg723SerfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP7 NM_003470.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

Genes affected

USP7 (HGNC:12630): (ubiquitin specific peptidase 7) The protein encoded by this gene belongs to the peptidase C19 family, which includes ubiquitinyl hydrolases. This protein deubiquitinates target proteins such as p53 (a tumor suppressor protein) and WASH (essential for endosomal protein recycling), and regulates their activities by counteracting the opposing ubiquitin ligase activity of proteins such as HDM2 and TRIM27, involved in the respective process. Mutations in this gene have been implicated in a neurodevelopmental disorder. [provided by RefSeq, Mar 2016]

USP7 Gene-Disease associations (from GenCC):

• Hao-Fountain syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Illumina
• Hao-Fountain syndrome due to USP7 mutation

  Inheritance: AD Classification: STRONG Submitted by: G2P

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-8901027-GCT-G is Pathogenic according to our data. Variant chr16-8901027-GCT-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 522827.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003470.3. 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
	USP7	NM_003470.3	MANE Select	c.2169_2170delAG	p.Arg723SerfsTer8	frameshift	Exon 20 of 31	NP_003461.2	Q93009-1
	USP7	NM_001286457.2		c.2121_2122delAG	p.Arg707SerfsTer8	frameshift	Exon 20 of 31	NP_001273386.2	Q93009-3
	USP7	NM_001321858.2		c.1995_1996delAG	p.Arg665SerfsTer8	frameshift	Exon 20 of 31	NP_001308787.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP7	ENST00000344836.9	TSL:1 MANE Select	c.2169_2170delAG	p.Arg723SerfsTer8	frameshift	Exon 20 of 31	ENSP00000343535.4	Q93009-1
	USP7	ENST00000381886.8	TSL:1	c.2121_2122delAG	p.Arg707SerfsTer8	frameshift	Exon 20 of 31	ENSP00000371310.4	Q93009-3
	USP7	ENST00000673704.1		c.2274_2275delAG	p.Arg758SerfsTer8	frameshift	Exon 20 of 31	ENSP00000501290.1	A0A669KBL1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hao-Fountain syndrome (1)
1	-	-	USP7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1555462347; hg19: chr16-8994884;