16-8963215-T-C

Variant names:

• chr16-8963215-T-C
• rs1045125836
• NM_003470.3:c.71A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003470.3(USP7):​c.71A>G​(p.Glu24Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000316 in 1,263,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E24V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: USP7 NM_003470.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.34
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12710643).

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.71A>G	p.Glu24Gly	missense	Exon 1 of 31	NP_003461.2	Q93009-1
	USP7-AS1	NR_184341.1		n.182+321T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP7	ENST00000344836.9	TSL:1 MANE Select	c.71A>G	p.Glu24Gly	missense	Exon 1 of 31	ENSP00000343535.4	Q93009-1
	USP7	ENST00000923082.1		c.71A>G	p.Glu24Gly	missense	Exon 1 of 31	ENSP00000593141.1
	USP7	ENST00000923081.1		c.71A>G	p.Glu24Gly	missense	Exon 1 of 31	ENSP00000593140.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000316 AC: 4 AN: 1263930 Hom.: 0 Cov.: 30 AF XY: 0.00000321 AC XY: 2 AN XY: 623806

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

African (AFR) AF: 0.00 AC: 0 AN: 24936

American (AMR) AF: 0.00 AC: 0 AN: 25308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20686

East Asian (EAS) AF: 0.00 AC: 0 AN: 23886

South Asian (SAS) AF: 0.0000139 AC: 1 AN: 71808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4284

European-Non Finnish (NFE) AF: 0.00000298 AC: 3 AN: 1007402

Other (OTH) AF: 0.00 AC: 0 AN: 49820

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000100253), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.052
Sift	Benign	0.14	T
Sift4G	Benign	0.27	T
Polyphen		0.016	B
Vest4		0.21
MutPred		0.24		Gain of sheet (P = 0.0073)
MVP		0.22
MPC		0.32
ClinPred		0.26	T
GERP RS		2.5
Varity_R		0.12
gMVP		0.30

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: rs1045125836; hg19: chr16-9057072;