X-49880529-G-A

Variant names:

• chrX-49880529-G-A
• rs782300135
• NM_001145073.3:c.222G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001145073.3(USP27X):​c.222G>A​(p.Thr74Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,054,289 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: USP27X NM_001145073.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.935
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-49880529-G-A is Benign according to our data. Variant chrX-49880529-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1012871.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.935 with no splicing effect.

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.222G>A	p.Thr74Thr	synonymous	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.222G>A	p.Thr74Thr	synonymous	Exon 1 of 1	ENSP00000483631.1	A6NNY8

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000190 AC: 2 AN: 1054289 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 345019

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000401 AC: 1 AN: 24918

American (AMR) AF: 0.00 AC: 0 AN: 27913

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18643

East Asian (EAS) AF: 0.00 AC: 0 AN: 27133

South Asian (SAS) AF: 0.00 AC: 0 AN: 49887

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37664

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 819639

Other (OTH) AF: 0.0000225 AC: 1 AN: 44401

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.2
DANN	Benign	0.90
PhyloP100		0.94

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: rs782300135; hg19: chrX-49645132; COSMIC: COSV71200886; COSMIC: COSV71200886;