Genetic Variant USP7:p.Ala12Thr (chr16-8963252-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_003470.3(USP7):c.34G>A(p.Ala12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

USP7
NM_003470.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.63

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06227547).

BP6

Variant 16-8963252-C-T is Benign according to our data. Variant chr16-8963252-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2572898.Status of the report is criteria_provided_single_submitter, 1 stars.

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.34G>A	p.Ala12Thr	missense	Exon 1 of 31	NP_003461.2	Q93009-1
	USP7-AS1	NR_184341.1		n.182+358C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP7	ENST00000344836.9	TSL:1 MANE Select	c.34G>A	p.Ala12Thr	missense	Exon 1 of 31	ENSP00000343535.4	Q93009-1
USP7	ENST00000923082.1		c.34G>A	p.Ala12Thr	missense	Exon 1 of 31	ENSP00000593141.1
USP7	ENST00000923081.1		c.34G>A	p.Ala12Thr	missense	Exon 1 of 31	ENSP00000593140.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1232230

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

607876

African (AFR)

AF:

0.00

AC:

AN:

24514

American (AMR)

AF:

0.00

AC:

AN:

23966

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19870

East Asian (EAS)

AF:

0.00

AC:

AN:

22780

South Asian (SAS)

AF:

0.00

AC:

AN:

68242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31826

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4080

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

989058

Other (OTH)

AF:

0.00

AC:

AN:

47894

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.72

M_CAP

Benign

0.084

MetaRNN

Benign

0.062

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

1.6

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.20

REVEL

Benign

0.10

Sift

Benign

0.64

Sift4G

Benign

0.56

Polyphen

0.012

Vest4

0.19

MutPred

0.061

Gain of phosphorylation at A12 (P = 0.0128)

MVP

0.15

MPC

0.26

ClinPred

0.14

GERP RS

2.5

Varity_R

0.042

gMVP

0.26

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over