Genetic Variant NM_003470.3:c.2719-234C>T (chr16-8897333-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003470.3(USP7):c.2719-234C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 484,000 control chromosomes in the GnomAD database, including 20,159 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 5414 hom., cov: 30)

Exomes 𝑓: 0.29 ( 14745 hom. )

Consequence

USP7
NM_003470.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.397

Publications

12 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 Gene-Disease associations (from GenCC):

Hao-Fountain syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Illumina
Hao-Fountain syndrome due to USP7 mutation
Inheritance: AD Classification: STRONG Submitted by: G2P

USP7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP7	NM_003470.3 link	c.2719-234C>T		intron_variant	Intron 25 of 30	ENST00000344836.9	NP_003461.2	Q93009-1Q6U8A4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP7	ENST00000344836.9 link	c.2719-234C>T		intron_variant	Intron 25 of 30	1	NM_003470.3	ENSP00000343535.4		Q93009-1

Frequencies

GnomAD3 genomes

AF:

0.260

AC:

39428

AN:

151706

Hom.:

5413

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.203

Gnomad AMR

AF:

0.277

Gnomad ASJ

AF:

0.303

Gnomad EAS

AF:

0.212

Gnomad SAS

AF:

0.336

Gnomad FIN

AF:

0.271

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.306

Gnomad OTH

AF:

0.250

GnomAD4 exome

AF:

0.295

AC:

97850

AN:

332176

Hom.:

14745

AF XY:

0.298

AC XY:

51960

AN XY:

174612

show subpopulations

African (AFR)

AF:

0.170

AC:

1704

AN:

10020

American (AMR)

AF:

0.296

AC:

3406

AN:

11524

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

3042

AN:

10182

East Asian (EAS)

AF:

0.247

AC:

5721

AN:

23198

South Asian (SAS)

AF:

0.312

AC:

9257

AN:

29642

European-Finnish (FIN)

AF:

0.274

AC:

6180

AN:

22596

Middle Eastern (MID)

AF:

0.286

AC:

425

AN:

1488

European-Non Finnish (NFE)

AF:

0.307

AC:

62639

AN:

204210

Other (OTH)

AF:

0.283

AC:

5476

AN:

19316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

3180

6361

9541

12722

15902

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

328

656

984

1312

1640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.260

AC:

39441

AN:

151824

Hom.:

5414

Cov.:

AF XY:

0.259

AC XY:

19192

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.169

AC:

7007

AN:

41416

American (AMR)

AF:

0.277

AC:

4217

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

1050

AN:

3466

East Asian (EAS)

AF:

0.212

AC:

1087

AN:

5132

South Asian (SAS)

AF:

0.336

AC:

1614

AN:

4806

European-Finnish (FIN)

AF:

0.271

AC:

2860

AN:

10538

Middle Eastern (MID)

AF:

0.269

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.307

AC:

20818

AN:

67918

Other (OTH)

AF:

0.250

AC:

525

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1421

2842

4263

5684

7105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

422

844

1266

1688

2110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.245

Hom.:

1851

Bravo

AF:

0.257

Asia WGS

AF:

0.295

AC:

1026

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.54

(source)

DANN

Benign

0.43

PhyloP100

-0.40

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over