NM_003470.3:c.12G>C

Variant names:

• chr16-8963274-C-G
• rs750093857
• NM_003470.3:c.12G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. 14/21 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.557
• Publications: 12 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 -16 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 2077808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 31 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.12G>C	p.Gln4His	missense	Exon 1 of 31	NP_003461.2	Q93009-1
	USP7-AS1	NR_184341.1		n.182+380C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP7	ENST00000344836.9	TSL:1 MANE Select	c.12G>C	p.Gln4His	missense	Exon 1 of 31	ENSP00000343535.4	Q93009-1
	USP7	ENST00000923082.1		c.12G>C	p.Gln4His	missense	Exon 1 of 31	ENSP00000593141.1
	USP7	ENST00000923081.1		c.12G>C	p.Gln4His	missense	Exon 1 of 31	ENSP00000593140.1

Frequencies

GnomAD3 genomes AF: 0.000208 AC: 31 AN: 148700 Hom.: 0 Cov.: 30

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

GnomAD2 exomes AF: 0.000942 AC: 66 AN: 70054 AF XY: 0.000863

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 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.: 0 Cov.: 26 AF XY: 0.000768 AC XY: 414 AN XY: 539348

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000923 AC: 20 AN: 21658

American (AMR) AF: 0.00208 AC: 41 AN: 19666

Ashkenazi Jewish (ASJ) AF: 0.000777 AC: 13 AN: 16728

East Asian (EAS) AF: 0.00114 AC: 21 AN: 18356

South Asian (SAS) AF: 0.00203 AC: 117 AN: 57624

European-Finnish (FIN) AF: 0.00154 AC: 37 AN: 24078

Middle Eastern (MID) AF: 0.000285 AC: 1 AN: 3510

European-Non Finnish (NFE) AF: 0.000552 AC: 492 AN: 891586

Other (OTH) AF: 0.000870 AC: 36 AN: 41402

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000208 AC: 31 AN: 148766 Hom.: 0 Cov.: 30 AF XY: 0.000207 AC XY: 15 AN XY: 72586

African (AFR) AF: 0.000122 AC: 5 AN: 41104

American (AMR) AF: 0.00120 AC: 18 AN: 14984

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

East Asian (EAS) AF: 0.000199 AC: 1 AN: 5028

South Asian (SAS) AF: 0.00 AC: 0 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000105 AC: 7 AN: 66904

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.000108 Hom.: 0

ExAC AF: 0.00189 AC: 55

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	USP7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.56
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.056
Sift	Benign	0.40	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.14		Loss of helix (P = 0.0626)
MVP		0.24
MPC		0.25
ClinPred		0.0038	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.033
gMVP		0.36
Mutation Taster		=92/8	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: rs750093857; hg19: chr16-9057131; COSMIC: COSV61213958; COSMIC: COSV61213958;