chrX-49880652-G-A

Variant names:

• chrX-49880652-G-A
• rs1924367562
• NM_001145073.3:c.345G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001145073.3(USP27X):​c.345G>A​(p.Met115Ile) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.5e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: USP27X NM_001145073.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30825016).

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.345G>A	p.Met115Ile	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.345G>A	p.Met115Ile	missense	Exon 1 of 1	ENSP00000483631.1	A6NNY8

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.48e-7 AC: 1 AN: 1054682 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 1 AN XY: 345146

African (AFR) AF: 0.00 AC: 0 AN: 24929

American (AMR) AF: 0.00 AC: 0 AN: 27925

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18648

East Asian (EAS) AF: 0.00 AC: 0 AN: 27177

South Asian (SAS) AF: 0.00 AC: 0 AN: 49891

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4091

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 819843

Other (OTH) AF: 0.00 AC: 0 AN: 44444

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.017	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.31	T
MutationAssessor	Benign	0.17	N
PhyloP100		10
PrimateAI	Uncertain	0.77	T
Sift4G	Benign	0.47	T
Polyphen		0.013	B
Vest4		0.55
MVP		0.56
GERP RS		3.9
Varity_R		0.48
gMVP		0.83
Mutation Taster		=44/56	disease causing

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: rs1924367562; hg19: chrX-49645255;