NM_003470.3:c.37G>A

Variant names:

• chr16-8963249-C-T
• NM_003470.3:c.37G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003470.3(USP7):​c.37G>A​(p.Gly13Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000081 in 1,235,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G13D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: USP7 NM_003470.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.05
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27581608).

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.37G>A	p.Gly13Ser	missense	Exon 1 of 31	NP_003461.2	Q93009-1
	USP7-AS1	NR_184341.1		n.182+355C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP7	ENST00000344836.9	TSL:1 MANE Select	c.37G>A	p.Gly13Ser	missense	Exon 1 of 31	ENSP00000343535.4	Q93009-1
	USP7	ENST00000923082.1		c.37G>A	p.Gly13Ser	missense	Exon 1 of 31	ENSP00000593141.1
	USP7	ENST00000923081.1		c.37G>A	p.Gly13Ser	missense	Exon 1 of 31	ENSP00000593140.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 8.10e-7 AC: 1 AN: 1235244 Hom.: 0 Cov.: 30 AF XY: 0.00000164 AC XY: 1 AN XY: 609450

African (AFR) AF: 0.00 AC: 0 AN: 24576

American (AMR) AF: 0.00 AC: 0 AN: 24054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19938

East Asian (EAS) AF: 0.00 AC: 0 AN: 22954

South Asian (SAS) AF: 0.00 AC: 0 AN: 68436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4160

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 990734

Other (OTH) AF: 0.00 AC: 0 AN: 48106

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.049
Eigen_PC	Benign	-0.058
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.34	N
REVEL	Benign	0.19
Sift	Benign	0.37	T
Sift4G	Benign	0.78	T
Polyphen		0.98	D
Vest4		0.33
MutPred		0.075		Loss of loop (P = 0.0073)
MVP		0.51
MPC		0.28
ClinPred		0.54	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.067
gMVP		0.21

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

hg19: chr16-9057106;