chr16-8963278-T-C

Variant names:

• chr16-8963278-T-C
• rs1272991796
• NM_003470.3:c.8A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003470.3(USP7):​c.8A>G​(p.His3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 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. H3Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: USP7 NM_003470.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.31
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17838225).

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.8A>G	p.His3Arg	missense	Exon 1 of 31	NP_003461.2	Q93009-1
	USP7-AS1	NR_184341.1		n.182+384T>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.8A>G	p.His3Arg	missense	Exon 1 of 31	ENSP00000343535.4	Q93009-1
	USP7	ENST00000923082.1		c.8A>G	p.His3Arg	missense	Exon 1 of 31	ENSP00000593141.1
	USP7	ENST00000923081.1		c.8A>G	p.His3Arg	missense	Exon 1 of 31	ENSP00000593140.1

Frequencies

GnomAD3 genomes AF: 0.00000678 AC: 1 AN: 147402 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000246

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1180898 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 582160

African (AFR) AF: 0.00 AC: 0 AN: 23382

American (AMR) AF: 0.00 AC: 0 AN: 22004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18400

East Asian (EAS) AF: 0.00 AC: 0 AN: 20492

South Asian (SAS) AF: 0.00 AC: 0 AN: 63726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 957376

Other (OTH) AF: 0.00 AC: 0 AN: 44992

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000678 AC: 1 AN: 147402 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 71870

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

African (AFR) AF: 0.0000246 AC: 1 AN: 40588

American (AMR) AF: 0.00 AC: 0 AN: 14874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00 AC: 0 AN: 4896

South Asian (SAS) AF: 0.00 AC: 0 AN: 4660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66596

Other (OTH) AF: 0.00 AC: 0 AN: 2038

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Benign	0.89
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.12
Sift	Benign	0.090	T
Sift4G	Benign	0.17	T
Polyphen		0.46	P
Vest4		0.29
MutPred		0.23		Gain of MoRF binding (P = 0.0018)
MVP		0.34
MPC		0.33
ClinPred		0.13	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.11
gMVP		0.36

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: rs1272991796; hg19: chr16-9057135;