X-47239077-G-C

Variant names:

• chrX-47239077-G-C
• rs183062376
• NM_001371072.1:c.184G>C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001371072.1(USP11):​c.184G>C​(p.Val62Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000726 in 1,207,129 control chromosomes in the GnomAD database, including 3 homozygotes. There are 286 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., 13 hem., cov: 24)
  • Exomes 𝑓: 0.00074 (3 hom. 273 hem.)
• Consequence: USP11 NM_001371072.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 1.45

Genes affected

USP11 (HGNC:12609): (ubiquitin specific peptidase 11) Protein ubiquitination controls many intracellular processes, including cell cycle progression, transcriptional activation, and signal transduction. This dynamic process, involving ubiquitin conjugating enzymes and deubiquitinating enzymes, adds and removes ubiquitin. Deubiquitinating enzymes are cysteine proteases that specifically cleave ubiquitin from ubiquitin-conjugated protein substrates. This gene encodes a deubiquitinating enzyme which lies in a gene cluster on chromosome Xp11.23 [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030721933).
• BS2: High Hemizygotes in GnomAd4 at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP11	NM_001371072.1	c.184G>C	p.Val62Leu	missense_variant	Exon 2 of 21	ENST00000377107.7	NP_001358001.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP11	ENST00000377107.7	c.184G>C	p.Val62Leu	missense_variant	Exon 2 of 21	1	NM_001371072.1	ENSP00000366311.2

Frequencies

GnomAD3 genomes AF: 0.000599 AC: 67 AN: 111802 Hom.: 0 Cov.: 24 AF XY: 0.000383 AC XY: 13 AN XY: 33966

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000950

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000662

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00105

Gnomad OTH AF: 0.00132

GnomAD3 exomes AF: 0.000476 AC: 83 AN: 174191 Hom.: 0 AF XY: 0.000402 AC XY: 24 AN XY: 59769

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000282

Gnomad FIN exome AF: 0.000545

Gnomad NFE exome AF: 0.000803

Gnomad OTH exome AF: 0.000462

GnomAD4 exome AF: 0.000739 AC: 809 AN: 1095275 Hom.: 3 Cov.: 30 AF XY: 0.000756 AC XY: 273 AN XY: 360917

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000200

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000355

Gnomad4 FIN exome AF: 0.000471

Gnomad4 NFE exome AF: 0.000874

Gnomad4 OTH exome AF: 0.000587

GnomAD4 genome AF: 0.000599 AC: 67 AN: 111854 Hom.: 0 Cov.: 24 AF XY: 0.000382 AC XY: 13 AN XY: 34028

Gnomad4 AFR AF: 0.000130

Gnomad4 AMR AF: 0.0000949

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000662

Gnomad4 NFE AF: 0.00105

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.000775 Hom.: 12

Bravo AF: 0.000529

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.000618 AC: 75

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:2

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.313G>C (p.V105L) alteration is located in exon 2 (coding exon 2) of the USP11 gene. This alteration results from a G to C substitution at nucleotide position 313, causing the valine (V) at amino acid position 105 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T;T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.031	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.075
Sift	Benign	0.14	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.015	.;B
Vest4		0.14
MutPred		0.51		.;Gain of sheet (P = 0.0477);
MVP		0.72
MPC		0.71
ClinPred		0.033	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs183062376; hg19: chrX-47098476;