16-8963274-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_003470.3(USP7):c.12G>C(p.Gln4His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000651 in 1,243,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00071 ( 0 hom. )

Consequence

USP7
NM_003470.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.557

Variant links:

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 links:

USP7-AS1 (HGNC:55379): (USP7 antisense RNA 1)

USP7-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in the USP7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 5.648 (above the threshold of 3.09). Trascript score misZ: 6.8588 (above the threshold of 3.09). GenCC associations: The gene is linked to Hao-Fountain syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.005593717).

BP6

Variant 16-8963274-C-G is Benign according to our data. Variant chr16-8963274-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2077808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8963274-C-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP7	NM_003470.3 link	c.12G>C	p.Gln4His	missense_variant	Exon 1 of 31	ENST00000344836.9	NP_003461.2	Q93009-1Q6U8A4
USP7-AS1	NR_184341.1 link	n.182+380C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP7	ENST00000344836.9 link	c.12G>C	p.Gln4His	missense_variant	Exon 1 of 31	1	NM_003470.3	ENSP00000343535.4		Q93009-1

Frequencies

GnomAD3 genomes

AF:

0.000208

AC:

AN:

148700

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00120

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000198

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000105

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000942

AC:

AN:

70054

Hom.:

AF XY:

0.000863

AC XY:

AN XY:

40540

show subpopulations

Gnomad AFR exome

AF:

0.00179

Gnomad AMR exome

AF:

0.00212

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00188

Gnomad SAS exome

AF:

0.000532

Gnomad FIN exome

AF:

0.000752

Gnomad NFE exome

AF:

0.000624

Gnomad OTH exome

AF:

0.000988

GnomAD4 exome

AF:

0.000711

AC:

778

AN:

1094608

Hom.:

Cov.:

AF XY:

0.000768

AC XY:

414

AN XY:

539348

show subpopulations

Gnomad4 AFR exome

AF:

0.000923

Gnomad4 AMR exome

AF:

0.00208

Gnomad4 ASJ exome

AF:

0.000777

Gnomad4 EAS exome

AF:

0.00114

Gnomad4 SAS exome

AF:

0.00203

Gnomad4 FIN exome

AF:

0.00154

Gnomad4 NFE exome

AF:

0.000552

Gnomad4 OTH exome

AF:

0.000870

GnomAD4 genome

AF:

0.000208

AC:

AN:

148766

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

AN XY:

72586

show subpopulations

Gnomad4 AFR

AF:

0.000122

Gnomad4 AMR

AF:

0.00120

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000199

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000105

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

ExAC

AF:

0.00189

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

USP7: BS1, BS2 -

USP7-related disorder

Benign:1

Jun 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.26

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.31

REVEL

Benign

0.056

Sift

Benign

0.40

Sift4G

Benign

0.50

Polyphen

0.0

Vest4

0.15

MutPred

0.14

Loss of helix (P = 0.0626);

MVP

0.24

MPC

0.25

ClinPred

0.0038

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.033

gMVP

0.36

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over