rs28382751

Positions:

• chrX-123911259-C-A
• chrX-123911259-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001167.4(XIAP):​c.*4078C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 106,268 control chromosomes in the GnomAD database, including 1,301 homozygotes. There are 5,727 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (1301 hom., 5727 hem., cov: 21)
  • Exomes 𝑓: 0.23 (3580 hom. 21461 hem.)
  • Failed GnomAD Quality Control
• Consequence: XIAP NM_001167.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.202

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-123911259-C-A is Benign according to our data. Variant chrX-123911259-C-A is described in ClinVar as [Benign]. Clinvar id is 367831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XIAP	NM_001167.4	c.*4078C>A		3_prime_UTR_variant	7/7	ENST00000371199.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XIAP	ENST00000371199.8	c.*4078C>A		3_prime_UTR_variant	7/7	1	NM_001167.4	P1
XIAP	ENST00000355640.3	c.*4078C>A		3_prime_UTR_variant	7/7	5		P1

Frequencies

GnomAD3 genomes AF: 0.178 AC: 18907 AN: 106214 Hom.: 1300 Cov.: 21 AF XY: 0.182 AC XY: 5722 AN XY: 31502

Gnomad AFR AF: 0.0792

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.191

GnomAD3 exomes AF: 0.238 AC: 21825 AN: 91765 Hom.: 1810 AF XY: 0.249 AC XY: 8275 AN XY: 33205

Gnomad AFR exome AF: 0.0653

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.372

Gnomad SAS exome AF: 0.392

Gnomad FIN exome AF: 0.245

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.229

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.235 AC: 49868 AN: 212360 Hom.: 3580 Cov.: 0 AF XY: 0.256 AC XY: 21461 AN XY: 83704

Gnomad4 AFR exome AF: 0.0820

Gnomad4 AMR exome AF: 0.208

Gnomad4 ASJ exome AF: 0.204

Gnomad4 EAS exome AF: 0.363

Gnomad4 SAS exome AF: 0.388

Gnomad4 FIN exome AF: 0.245

Gnomad4 NFE exome AF: 0.195

Gnomad4 OTH exome AF: 0.222

GnomAD4 genome AF: 0.178 AC: 18911 AN: 106268 Hom.: 1301 Cov.: 21 AF XY: 0.181 AC XY: 5727 AN XY: 31560

Gnomad4 AFR AF: 0.0792

Gnomad4 AMR AF: 0.214

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.337

Gnomad4 SAS AF: 0.382

Gnomad4 FIN AF: 0.248

Gnomad4 NFE AF: 0.192

Gnomad4 OTH AF: 0.197

Alfa AF: 0.0663 Hom.: 259

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs28382751; hg19: chrX-123045109;