rs886038211

chrX-49881448-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001145073.3(USP27X):c.1141T>C(p.Tyr381His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 9/15 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: USP27X NM_001145073.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02

Genes affected

USP27X (HGNC:13486): (ubiquitin specific peptidase 27 X-linked) This gene encodes a member of the peptidase protein family. The encoded protein functions as a deubiquitinase that is involved in upregulation of the pro-apoptotic Bim protein. This protein may act as a tumor suppressor by increasing levels of Bim to counteract anti-apoptotic signals in cancer cells. Mutations in this gene have been associated with X-linked cognitive disability. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant X-49881448-T-C is Pathogenic according to our data. Variant chrX-49881448-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 254685.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-49881448-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP27X	NM_001145073.3	c.1141T>C	p.Tyr381His	missense_variant	1/1	ENST00000621775.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP27X	ENST00000621775.2	c.1141T>C	p.Tyr381His	missense_variant	1/1		NM_001145073.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, X-linked 105 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	28
Dann	Benign	0.88
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.4	H
PrimateAI	Pathogenic	0.91	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.70
GERP RS		4.4
Varity_R		0.18
gMVP		0.99

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: rs886038211; hg19: chrX-49646051;