X-49880529-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_001145073.3(USP27X):​c.222G>C​(p.Thr74Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000352 in 1,165,807 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T74T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.000028 (0 hom. 15 hem.)
• Consequence: USP27X NM_001145073.3 synonymous
• Clinical Significance: Not reported in ClinVar
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP7: Synonymous conserved (PhyloP=0.935 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

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>C	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>C	p.Thr74Thr	synonymous	Exon 1 of 1	ENSP00000483631.1	A6NNY8

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 11 AN: 111517 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD2 exomes AF: 0.0000608 AC: 7 AN: 115130 AF XY: 0.000145

Gnomad AFR exome AF: 0.000626

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000285 AC: 30 AN: 1054290 Hom.: 0 Cov.: 31 AF XY: 0.0000435 AC XY: 15 AN XY: 345020

African (AFR) AF: 0.000642 AC: 16 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: 0.000261 AC: 13 AN: 49887

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37665

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

GnomAD4 genome AF: 0.0000986 AC: 11 AN: 111517 Hom.: 0 Cov.: 24 AF XY: 0.0000593 AC XY: 2 AN XY: 33699

African (AFR) AF: 0.000360 AC: 11 AN: 30573

American (AMR) AF: 0.00 AC: 0 AN: 10629

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3537

South Asian (SAS) AF: 0.00 AC: 0 AN: 2612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6001

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53095

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.9
DANN	Benign	0.82
PhyloP100		0.94
Mutation Taster		=100/0	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: rs782300135; hg19: chrX-49645132;