NM_003470.3:c.3202+18_3202+19insT

Variant names:

• chr16-8894531-G-GA
• rs534626904
• NM_003470.3:c.3202+18_3202+19insT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_003470.3(USP7):​c.3202+18_3202+19insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,465,380 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000097 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: USP7 NM_003470.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.90
• 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 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 16-8894531-G-GA is Benign according to our data. Variant chr16-8894531-G-GA is described in ClinVar as Likely_benign. ClinVar VariationId is 3697380.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 6 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+18_3202+19insT		intron	N/A	NP_003461.2	Q93009-1
	USP7	NM_001286457.2		c.3154+18_3154+19insT		intron	N/A	NP_001273386.2	Q93009-3
	USP7	NM_001321858.2		c.3028+18_3028+19insT		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+18_3202+19insT		intron	N/A	ENSP00000343535.4	Q93009-1
	USP7	ENST00000381886.8	TSL:1	c.3154+18_3154+19insT		intron	N/A	ENSP00000371310.4	Q93009-3
	USP7	ENST00000673704.1		c.3307+18_3307+19insT		intron	N/A	ENSP00000501290.1	A0A669KBL1

Frequencies

GnomAD3 genomes AF: 0.0000968 AC: 6 AN: 61990 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000904

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000351

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000127

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000149 AC: 15 AN: 100894 AF XY: 0.000146

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000179

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000145

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.0000734 AC: 103 AN: 1403358 Hom.: 0 Cov.: 36 AF XY: 0.0000688 AC XY: 48 AN XY: 697838

African (AFR) AF: 0.0000307 AC: 1 AN: 32558

American (AMR) AF: 0.0000759 AC: 3 AN: 39520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24888

East Asian (EAS) AF: 0.0000574 AC: 2 AN: 34820

South Asian (SAS) AF: 0.000169 AC: 14 AN: 83062

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4038

European-Non Finnish (NFE) AF: 0.0000743 AC: 80 AN: 1076426

Other (OTH) AF: 0.0000347 AC: 2 AN: 57670

GnomAD4 genome AF: 0.0000967 AC: 6 AN: 62022 Hom.: 0 Cov.: 33 AF XY: 0.0000984 AC XY: 3 AN XY: 30486

African (AFR) AF: 0.0000902 AC: 2 AN: 22180

American (AMR) AF: 0.00 AC: 0 AN: 4708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1230

East Asian (EAS) AF: 0.000352 AC: 1 AN: 2838

South Asian (SAS) AF: 0.00 AC: 0 AN: 1938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 80

European-Non Finnish (NFE) AF: 0.000127 AC: 3 AN: 23704

Other (OTH) AF: 0.00 AC: 0 AN: 814

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Likely 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		-1.9
Mutation Taster		=100/0	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: rs534626904; hg19: chr16-8988388;