rs28382751

Variant names:

• chrX-123911259-C-A
• rs28382751
• NM_001167.4:c.*4078C>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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:3
• Conservation: PhyloP100: 0.202
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• 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 rank	MANE	Protein	UniProt
XIAP	NM_001167.4	c.*4078C>A		3_prime_UTR_variant	Exon 7 of 7	ENST00000371199.8	NP_001158.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000371199.8	c.*4078C>A		3_prime_UTR_variant	Exon 7 of 7	1	NM_001167.4	ENSP00000360242.3
XIAP	ENST00000355640.3	c.*4078C>A		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000347858.3

Frequencies

GnomAD3 genomes AF: 0.178 AC: 18907 AN: 106214 Hom.: 1300 Cov.: 21

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

GnomAD2 exomes AF: 0.238 AC: 21825 AN: 91765 AF XY: 0.249

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 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

African (AFR) AF: 0.0820 AC: 488 AN: 5953

American (AMR) AF: 0.208 AC: 4392 AN: 21166

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 1603 AN: 7870

East Asian (EAS) AF: 0.363 AC: 2419 AN: 6657

South Asian (SAS) AF: 0.388 AC: 13714 AN: 35367

European-Finnish (FIN) AF: 0.245 AC: 2295 AN: 9349

Middle Eastern (MID) AF: 0.282 AC: 227 AN: 804

European-Non Finnish (NFE) AF: 0.195 AC: 22447 AN: 114918

Other (OTH) AF: 0.222 AC: 2283 AN: 10276

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

African (AFR) AF: 0.0792 AC: 2134 AN: 26931

American (AMR) AF: 0.214 AC: 2182 AN: 10173

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 497 AN: 2631

East Asian (EAS) AF: 0.337 AC: 1160 AN: 3439

South Asian (SAS) AF: 0.382 AC: 985 AN: 2577

European-Finnish (FIN) AF: 0.248 AC: 1410 AN: 5689

Middle Eastern (MID) AF: 0.298 AC: 64 AN: 215

European-Non Finnish (NFE) AF: 0.192 AC: 10085 AN: 52499

Other (OTH) AF: 0.197 AC: 285 AN: 1444

Alfa AF: 0.0663 Hom.: 259

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 14, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.58
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

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: rs28382751; hg19: chrX-123045109;