16-8894529-CGGG-CGGGG

Variant names:

• chr16-8894529-C-CG
• rs3214650
• NM_003470.3:c.3202+20dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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

• Frequency:
  • Genomes: 𝑓 0.46 (17865 hom., cov: 0)
  • Exomes 𝑓: 0.46 (99961 hom.)
• Consequence: USP7 NM_003470.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 -16 ACMG points.

• BP6: Variant 16-8894529-C-CG is Benign according to our data. Variant chr16-8894529-C-CG is described in ClinVar as Benign. ClinVar VariationId is 1637214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

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+20dupC		intron	N/A	NP_003461.2	Q93009-1
	USP7	NM_001286457.2		c.3154+20dupC		intron	N/A	NP_001273386.2	Q93009-3
	USP7	NM_001321858.2		c.3028+20dupC		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+21insC		intron	N/A	ENSP00000343535.4	Q93009-1
	USP7	ENST00000381886.8	TSL:1	c.3154+20_3154+21insC		intron	N/A	ENSP00000371310.4	Q93009-3
	USP7	ENST00000673704.1		c.3307+20_3307+21insC		intron	N/A	ENSP00000501290.1	A0A669KBL1

Frequencies

GnomAD3 genomes AF: 0.462 AC: 69583 AN: 150752 Hom.: 17868 Cov.: 0

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.515

Gnomad EAS AF: 0.712

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.459

GnomAD2 exomes AF: 0.442 AC: 93393 AN: 211410 AF XY: 0.449

Gnomad AFR exome AF: 0.213

Gnomad AMR exome AF: 0.386

Gnomad ASJ exome AF: 0.413

Gnomad EAS exome AF: 0.569

Gnomad FIN exome AF: 0.505

Gnomad NFE exome AF: 0.451

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.463 AC: 616975 AN: 1332954 Hom.: 99961 Cov.: 0 AF XY: 0.465 AC XY: 308167 AN XY: 663390

African (AFR) AF: 0.198 AC: 6252 AN: 31594

American (AMR) AF: 0.398 AC: 16183 AN: 40662

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 10268 AN: 23958

East Asian (EAS) AF: 0.561 AC: 19781 AN: 35234

South Asian (SAS) AF: 0.504 AC: 38679 AN: 76704

European-Finnish (FIN) AF: 0.504 AC: 23017 AN: 45704

Middle Eastern (MID) AF: 0.427 AC: 1661 AN: 3892

European-Non Finnish (NFE) AF: 0.467 AC: 476106 AN: 1019926

Other (OTH) AF: 0.453 AC: 25028 AN: 55280

GnomAD4 genome AF: 0.461 AC: 69601 AN: 150860 Hom.: 17865 Cov.: 0 AF XY: 0.467 AC XY: 34411 AN XY: 73614

African (AFR) AF: 0.223 AC: 9150 AN: 41080

American (AMR) AF: 0.458 AC: 6970 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 1781 AN: 3458

East Asian (EAS) AF: 0.712 AC: 3611 AN: 5070

South Asian (SAS) AF: 0.609 AC: 2899 AN: 4762

European-Finnish (FIN) AF: 0.613 AC: 6325 AN: 10322

Middle Eastern (MID) AF: 0.407 AC: 118 AN: 290

European-Non Finnish (NFE) AF: 0.551 AC: 37263 AN: 67676

Other (OTH) AF: 0.461 AC: 965 AN: 2092

Alfa AF: 0.474 Hom.: 1411

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hao-Fountain syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

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: rs3214650; hg19: chr16-8988386; COSMIC: COSV106062155; COSMIC: COSV106062155;