NM_001145073.3:c.94G>A

Variant names:

• chrX-49880401-G-A
• rs369669737
• NM_001145073.3:c.94G>A

Variant summary

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

The NM_001145073.3(USP27X):​c.94G>A​(p.Glu32Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000257 in 1,166,468 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: USP27X NM_001145073.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.78
• Publications: 0 publications found

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]

USP27X Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 105

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability

  Inheritance: XL Classification: LIMITED Submitted by: ClinGen

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=0.091765136).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145073.3. 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
	USP27X	NM_001145073.3	MANE Select	c.94G>A	p.Glu32Lys	missense	Exon 1 of 1	NP_001138545.1	A6NNY8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP27X	ENST00000621775.2	TSL:6 MANE Select	c.94G>A	p.Glu32Lys	missense	Exon 1 of 1	ENSP00000483631.1	A6NNY8

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112529 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000278

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 AF: 0.00000190 AC: 2 AN: 1053939 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 344719

African (AFR) AF: 0.00 AC: 0 AN: 24908

American (AMR) AF: 0.00 AC: 0 AN: 27898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18642

East Asian (EAS) AF: 0.00 AC: 0 AN: 27116

South Asian (SAS) AF: 0.00 AC: 0 AN: 49858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37627

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4089

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 819420

Other (OTH) AF: 0.0000451 AC: 2 AN: 44381

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112529 Hom.: 0 Cov.: 24 AF XY: 0.0000288 AC XY: 1 AN XY: 34681

African (AFR) AF: 0.00 AC: 0 AN: 30934

American (AMR) AF: 0.00 AC: 0 AN: 10722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.000278 AC: 1 AN: 3593

South Asian (SAS) AF: 0.00 AC: 0 AN: 2715

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6169

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53315

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability, X-linked 105 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.85
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.092	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.8
PrimateAI	Uncertain	0.50	T
Sift4G	Benign	0.83	T
Polyphen		0.051	B
Vest4		0.26
MVP		0.043
GERP RS		5.0
Varity_R		0.30
gMVP		0.59
Mutation Taster		=99/1	polymorphism

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: rs369669737; hg19: chrX-49645004;