16-8894529-C-CGG

Variant names:

• chr16-8894529-C-CGG
• rs3214650
• NM_003470.3:c.3202+19_3202+20dupCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_003470.3(USP7):​c.3202+19_3202+20dupCC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0057 (2 hom.)
• Consequence: USP7 NM_003470.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.21
• 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: Ambry Genetics, Illumina, ClinGen
• Hao-Fountain syndrome due to USP7 mutation

  Inheritance: AD Classification: STRONG Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 16-8894529-C-CGG is Benign according to our data. Variant chr16-8894529-C-CGG is described in ClinVar as Benign. ClinVar VariationId is 1971378.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00297 (449/151060) while in subpopulation EAS AF = 0.0191 (97/5082). AF 95% confidence interval is 0.016. There are 2 homozygotes in GnomAd4. There are 216 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 449 AD gene.

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.3202+19_3202+20dupCC		intron	N/A	NP_003461.2	Q93009-1
	USP7	NM_001286457.2		c.3154+19_3154+20dupCC		intron	N/A	NP_001273386.2	Q93009-3
	USP7	NM_001321858.2		c.3028+19_3028+20dupCC		intron	N/A	NP_001308787.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP7	ENST00000344836.9	TSL:1 MANE Select	c.3202+20_3202+21insCC		intron	N/A	ENSP00000343535.4	Q93009-1
	USP7	ENST00000381886.8	TSL:1	c.3154+20_3154+21insCC		intron	N/A	ENSP00000371310.4	Q93009-3
	USP7	ENST00000673704.1		c.3307+20_3307+21insCC		intron	N/A	ENSP00000501290.1	A0A669KBL1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 450 AN: 150952 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00296

Gnomad ASJ AF: 0.00318

Gnomad EAS AF: 0.0192

Gnomad SAS AF: 0.00691

Gnomad FIN AF: 0.000772

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00193

GnomAD2 exomes AF: 0.00685 AC: 1448 AN: 211410 AF XY: 0.00671

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00445

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.0316

Gnomad FIN exome AF: 0.00387

Gnomad NFE exome AF: 0.00481

Gnomad OTH exome AF: 0.00420

GnomAD4 exome AF: 0.00574 AC: 7444 AN: 1296800 Hom.: 2 Cov.: 0 AF XY: 0.00577 AC XY: 3727 AN XY: 645542

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

African (AFR) AF: 0.00287 AC: 91 AN: 31744

American (AMR) AF: 0.00441 AC: 177 AN: 40150

Ashkenazi Jewish (ASJ) AF: 0.00414 AC: 97 AN: 23430

East Asian (EAS) AF: 0.0230 AC: 772 AN: 33508

South Asian (SAS) AF: 0.00965 AC: 718 AN: 74440

European-Finnish (FIN) AF: 0.00731 AC: 325 AN: 44464

Middle Eastern (MID) AF: 0.00603 AC: 23 AN: 3814

European-Non Finnish (NFE) AF: 0.00495 AC: 4912 AN: 991516

Other (OTH) AF: 0.00612 AC: 329 AN: 53734

⚠️ 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: 0.00297 AC: 449 AN: 151060 Hom.: 2 Cov.: 0 AF XY: 0.00293 AC XY: 216 AN XY: 73732

African (AFR) AF: 0.00229 AC: 94 AN: 41134

American (AMR) AF: 0.00295 AC: 45 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00318 AC: 11 AN: 3460

East Asian (EAS) AF: 0.0191 AC: 97 AN: 5082

South Asian (SAS) AF: 0.00671 AC: 32 AN: 4770

European-Finnish (FIN) AF: 0.000772 AC: 8 AN: 10360

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.00229 AC: 155 AN: 67732

Other (OTH) AF: 0.00239 AC: 5 AN: 2094

Alfa AF: 0.0130 Hom.: 1411

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3214650; hg19: chr16-8988386; COSMIC: COSV106062156; COSMIC: COSV106062156;