chr16-8963226-G-A

Variant names:

• chr16-8963226-G-A
• rs374020920
• NM_003470.3:c.60C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_003470.3(USP7):​c.60C>T​(p.Pro20Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0058 in 1,409,262 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (4 hom., cov: 30)
  • Exomes 𝑓: 0.0059 (69 hom.)
• Consequence: USP7 NM_003470.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.484
• Publications: 3 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 16-8963226-G-A is Benign according to our data. Variant chr16-8963226-G-A is described in ClinVar as Benign. ClinVar VariationId is 2043545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.484 with no splicing effect.
• BS2: High AC in GnomAd4 at 734 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.60C>T	p.Pro20Pro	synonymous	Exon 1 of 31	NP_003461.2	Q93009-1
	USP7-AS1	NR_184341.1		n.182+332G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP7	ENST00000344836.9	TSL:1 MANE Select	c.60C>T	p.Pro20Pro	synonymous	Exon 1 of 31	ENSP00000343535.4	Q93009-1
	USP7	ENST00000923082.1		c.60C>T	p.Pro20Pro	synonymous	Exon 1 of 31	ENSP00000593141.1
	USP7	ENST00000923081.1		c.60C>T	p.Pro20Pro	synonymous	Exon 1 of 31	ENSP00000593140.1

Frequencies

GnomAD3 genomes AF: 0.00490 AC: 736 AN: 150356 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.00107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00192

Gnomad ASJ AF: 0.0483

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00916

Gnomad FIN AF: 0.00120

Gnomad MID AF: 0.0321

Gnomad NFE AF: 0.00603

Gnomad OTH AF: 0.0112

GnomAD2 exomes AF: 0.00907 AC: 777 AN: 85666 AF XY: 0.00966

Gnomad AFR exome AF: 0.00300

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.0470

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00173

Gnomad NFE exome AF: 0.00679

Gnomad OTH exome AF: 0.00993

GnomAD4 exome AF: 0.00592 AC: 7446 AN: 1258806 Hom.: 69 Cov.: 30 AF XY: 0.00634 AC XY: 3936 AN XY: 621224

African (AFR) AF: 0.000562 AC: 14 AN: 24906

American (AMR) AF: 0.00124 AC: 31 AN: 25006

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 929 AN: 20542

East Asian (EAS) AF: 0.00 AC: 0 AN: 23782

South Asian (SAS) AF: 0.0111 AC: 787 AN: 71112

European-Finnish (FIN) AF: 0.00165 AC: 58 AN: 35136

Middle Eastern (MID) AF: 0.0180 AC: 75 AN: 4158

European-Non Finnish (NFE) AF: 0.00514 AC: 5164 AN: 1004636

Other (OTH) AF: 0.00783 AC: 388 AN: 49528

GnomAD4 genome AF: 0.00488 AC: 734 AN: 150456 Hom.: 4 Cov.: 30 AF XY: 0.00482 AC XY: 354 AN XY: 73512

African (AFR) AF: 0.00107 AC: 44 AN: 41314

American (AMR) AF: 0.00192 AC: 29 AN: 15126

Ashkenazi Jewish (ASJ) AF: 0.0483 AC: 167 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5050

South Asian (SAS) AF: 0.00938 AC: 45 AN: 4796

European-Finnish (FIN) AF: 0.00120 AC: 12 AN: 9966

Middle Eastern (MID) AF: 0.0276 AC: 8 AN: 290

European-Non Finnish (NFE) AF: 0.00603 AC: 407 AN: 67462

Other (OTH) AF: 0.0106 AC: 22 AN: 2084

Alfa AF: 0.00543 Hom.: 3

Bravo AF: 0.00455

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Uncertain	0.98
PhyloP100		0.48
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
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: rs374020920; hg19: chr16-9057083; COSMIC: COSV61213926; COSMIC: COSV61213926;