X-123886506-G-C

Variant names:

• chrX-123886506-G-C
• rs777303823
• NM_001167.4:c.844G>C

Variant summary

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

The NM_001167.4(XIAP):​c.844G>C​(p.Glu282Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000916 in 1,091,479 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E282K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: XIAP NM_001167.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.34
• Publications: 1 publications found

Genes affected

XIAP (HGNC:592): (X-linked inhibitor of apoptosis) This gene encodes a protein that belongs to a family of apoptotic suppressor proteins. Members of this family share a conserved motif termed, baculovirus IAP repeat, which is necessary for their anti-apoptotic function. This protein functions through binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2 and inhibits apoptosis induced by menadione, a potent inducer of free radicals, and interleukin 1-beta converting enzyme. This protein also inhibits at least two members of the caspase family of cell-death proteases, caspase-3 and caspase-7. Mutations in this gene are the cause of X-linked lymphoproliferative syndrome. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 2 and 11.[provided by RefSeq, Feb 2011]

XIAP Gene-Disease associations (from GenCC):

• X-linked lymphoproliferative disease due to XIAP deficiency

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	NM_001167.4	MANE Select	c.844G>C	p.Glu282Gln	missense	Exon 2 of 7	NP_001158.2
	XIAP	NM_001204401.2		c.844G>C	p.Glu282Gln	missense	Exon 2 of 7	NP_001191330.1
	XIAP	NM_001378590.1		c.844G>C	p.Glu282Gln	missense	Exon 2 of 7	NP_001365519.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	ENST00000371199.8	TSL:1 MANE Select	c.844G>C	p.Glu282Gln	missense	Exon 2 of 7	ENSP00000360242.3
	XIAP	ENST00000497640.1	TSL:1	n.100-2113G>C		intron	N/A
	XIAP	ENST00000355640.3	TSL:5	c.844G>C	p.Glu282Gln	missense	Exon 2 of 7	ENSP00000347858.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.16e-7 AC: 1 AN: 1091479 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360797

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

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54135

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33922

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842088

Other (OTH) AF: 0.00 AC: 0 AN: 46048

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked lymphoproliferative disease due to XIAP deficiency Uncertain:1

May 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 856103). This variant has not been reported in the literature in individuals affected with XIAP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 282 of the XIAP protein (p.Glu282Gln).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.094	T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	-0.0094	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.54
Sift	Benign	0.12	T
Sift4G	Uncertain	0.056	T
Polyphen		0.99	D
Vest4		0.52
MutPred		0.65		Gain of MoRF binding (P = 0.0457)
MVP		0.64
MPC		0.79
ClinPred		0.83	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.78
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs777303823; hg19: chrX-123020356;