X-47233041-G-C

Variant names:

• chrX-47233041-G-C
• rs2055352211
• ENST00000218348.7:c.127G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000218348.7(USP11):​c.127G>C​(p.Ala43Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A43A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: USP11 ENST00000218348.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15220651).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP11	NM_001371072.1	c.-3G>C		5_prime_UTR_variant	Exon 1 of 21	ENST00000377107.7	NP_001358001.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP11	ENST00000218348.7	c.127G>C	p.Ala43Pro	missense_variant	Exon 1 of 21	1		ENSP00000218348.3
USP11	ENST00000377107	c.-3G>C		5_prime_UTR_variant	Exon 1 of 21	1	NM_001371072.1	ENSP00000366311.2
USP11	ENST00000469080.5	n.12G>C		non_coding_transcript_exon_variant	Exon 1 of 19	1
USP11	ENST00000478596.5	n.58G>C		non_coding_transcript_exon_variant	Exon 1 of 4	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.127G>C (p.A43P) alteration is located in exon 1 (coding exon 1) of the USP11 gene. This alteration results from a G to C substitution at nucleotide position 127, causing the alanine (A) at amino acid position 43 to be replaced by a proline (P). 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	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.10
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.058	T
Polyphen		0.77	P
Vest4		0.16
MutPred		0.42		Loss of helix (P = 0.0041);
MVP		0.51
MPC		1.1
ClinPred		0.17	T
GERP RS		2.7
Varity_R		0.13
gMVP		0.59

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: rs2055352211; hg19: chrX-47092440;