16-8963255-TCTGCTGCTG-TCTGCTG

Variant names:

• chr16-8963255-TCTG-T
• rs749570604
• NM_003470.3:c.28_30delCAG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_003470.3(USP7):​c.28_30delCAG​(p.Gln10del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,363,576 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: USP7 NM_003470.3 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 3.39
• Publications: 1 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-AS1 (HGNC:55379): (USP7 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003470.3

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.28_30delCAG	p.Gln10del	conservative_inframe_deletion	Exon 1 of 31	NP_003461.2	Q93009-1
	USP7-AS1	NR_184341.1		n.182+380_182+382delCTG		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP7	ENST00000344836.9	TSL:1 MANE Select	c.28_30delCAG	p.Gln10del	conservative_inframe_deletion	Exon 1 of 31	ENSP00000343535.4	Q93009-1
	USP7	ENST00000923082.1		c.28_30delCAG	p.Gln10del	conservative_inframe_deletion	Exon 1 of 31	ENSP00000593141.1
	USP7	ENST00000923081.1		c.28_30delCAG	p.Gln10del	conservative_inframe_deletion	Exon 1 of 31	ENSP00000593140.1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 4 AN: 149172 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00141 AC: 109 AN: 77186 AF XY: 0.00136

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.000312

Gnomad EAS exome AF: 0.00247

Gnomad FIN exome AF: 0.00207

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.000460

GnomAD4 exome AF: 0.00122 AC: 1482 AN: 1214320 Hom.: 0 AF XY: 0.00129 AC XY: 772 AN XY: 598308

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

African (AFR) AF: 0.000868 AC: 21 AN: 24204

American (AMR) AF: 0.00234 AC: 55 AN: 23490

Ashkenazi Jewish (ASJ) AF: 0.00171 AC: 33 AN: 19346

East Asian (EAS) AF: 0.00153 AC: 34 AN: 22290

South Asian (SAS) AF: 0.00288 AC: 190 AN: 65968

European-Finnish (FIN) AF: 0.00330 AC: 102 AN: 30880

Middle Eastern (MID) AF: 0.00173 AC: 7 AN: 4036

European-Non Finnish (NFE) AF: 0.000991 AC: 968 AN: 977122

Other (OTH) AF: 0.00153 AC: 72 AN: 46984

⚠️ 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 AF: 0.0000268 AC: 4 AN: 149256 Hom.: 0 Cov.: 30 AF XY: 0.0000137 AC XY: 1 AN XY: 72888

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

African (AFR) AF: 0.00 AC: 0 AN: 41068

American (AMR) AF: 0.000133 AC: 2 AN: 15060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.00 AC: 0 AN: 5014

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.000105 AC: 1 AN: 9528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67098

Other (OTH) AF: 0.00 AC: 0 AN: 2074

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000101728), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	1	USP7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4
Mutation Taster		=85/15	polymorphism

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: rs749570604; hg19: chr16-9057112;