NM_003470.3:c.7C>T

Variant names:

• chr16-8963279-G-A
• rs901790687
• NM_003470.3:c.7C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003470.3(USP7):​c.7C>T​(p.His3Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,324,036 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000047 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: USP7 NM_003470.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.30
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14324182).
• BS2: High AC in GnomAd4 at 7 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.7C>T	p.His3Tyr	missense	Exon 1 of 31	NP_003461.2	Q93009-1
	USP7-AS1	NR_184341.1		n.182+385G>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.7C>T	p.His3Tyr	missense	Exon 1 of 31	ENSP00000343535.4	Q93009-1
	USP7	ENST00000923082.1		c.7C>T	p.His3Tyr	missense	Exon 1 of 31	ENSP00000593141.1
	USP7	ENST00000923081.1		c.7C>T	p.His3Tyr	missense	Exon 1 of 31	ENSP00000593140.1

Frequencies

GnomAD3 genomes AF: 0.0000470 AC: 7 AN: 148846 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000255 AC: 3 AN: 1175190 Hom.: 0 Cov.: 23 AF XY: 0.00000173 AC XY: 1 AN XY: 579182

African (AFR) AF: 0.0000431 AC: 1 AN: 23228

American (AMR) AF: 0.00 AC: 0 AN: 21726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18272

East Asian (EAS) AF: 0.00 AC: 0 AN: 20200

South Asian (SAS) AF: 0.00 AC: 0 AN: 63126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3688

European-Non Finnish (NFE) AF: 0.00000210 AC: 2 AN: 954016

Other (OTH) AF: 0.00 AC: 0 AN: 44726

GnomAD4 genome AF: 0.0000470 AC: 7 AN: 148846 Hom.: 0 Cov.: 30 AF XY: 0.0000551 AC XY: 4 AN XY: 72594

African (AFR) AF: 0.000171 AC: 7 AN: 41018

American (AMR) AF: 0.00 AC: 0 AN: 14986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 5076

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66972

Other (OTH) AF: 0.00 AC: 0 AN: 2050

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.11
Sift	Benign	0.064	T
Sift4G	Uncertain	0.047	D
Polyphen		0.27	B
Vest4		0.34
MutPred		0.13		Gain of phosphorylation at H3 (P = 0.0505)
MVP		0.28
MPC		0.31
ClinPred		0.30	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.14
gMVP		0.31
Mutation Taster		=73/27	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: rs901790687; hg19: chr16-9057136;